Skip to main content
SpringerLink
Log in
Book cover

Neurotoxicity of Metals pp 113–142Cite as

Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

  • Chapter
  • First Online:

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 18))

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn—demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Åberg D, Johansson P, Isgaard J, Wallin A, Johansson J-O, Andreasson U, Blennow K, Zetterberg H, Åberg DN, Svensson J. Increased cerebrospinal fluid level of insulin-like growth factor-II in male patients with Alzheimer’s disease. Journal of Alzheimer’s disease : JAD. 2015;48(3):637–46.

    Article  PubMed  CAS  Google Scholar 

  • Adem A, Ekblom J, Gillberg PG, Jossan SS, Höög A, Winblad B, Aquilonius SM, Wang LH, Sara V. Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis. J Neural Transm. 1994;97(1):73–84.

    Article  CAS  Google Scholar 

  • Aleman I. Insulin-like growth factor-1 and central neurodegenerative diseases. Endocrinol Metab Clin N Am. 2012;41(2):395–408.

    Article  CAS  Google Scholar 

  • Alexi T, Hughes PE, van Roon-Mom WM, Faull RL, Williams CE, Clark RG, Gluckman PD. The IGF-I amino-terminal tripeptide glycine-proline-glutamate (GPE) is neuroprotective to striatum in the quinolinic acid lesion animal model of Huntington’s disease. Exp Neurol. 1999;159(1):84–97.

    Article  CAS  PubMed  Google Scholar 

  • Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, Cao M, Corti S, Hedlund E. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. Sci Rep. 2016;6:25960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis. 2001;8(3):479–91.

    Article  CAS  PubMed  Google Scholar 

  • Arrasate M, Finkbeiner S. Protein aggregates in Huntington’s disease. Exp Neurol. 2011;238(1):1–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Aschner M, Erikson KM, Hernández E, Hernández E, Tjalkens R. Manganese and its role in Parkinson’s disease: from transport to neuropathology. NeuroMolecular Med. 2009;11(4):252–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayadi AE, Zigmond MJ, Smith AD. IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res. 2016;234(7):1863–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bae J-H, Jang B-C, Suh S-I, Ha E, Baik H, Kim S-S, Lee M-y, Shin D-H. Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3K/Akt pathways in BV2 microglial cells. Neurosci Lett. 2006;398(1–2):151–4.

    Article  CAS  PubMed  Google Scholar 

  • Baly DL (1984). Effect of manganese deficiency on insulin secretion and carbohydrate Heomostasis in rats. JNutrition.

    Google Scholar 

  • Baly DL, Keen CL, Hurley LS. Effects of manganese deficiency on pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity and carbohydrate homeostasis in adult rats. Biol Trace Elem Res. 1986;11(1):201–12.

    Article  CAS  PubMed  Google Scholar 

  • Baly DL, Lee I, Doshi R. Mechanism of decreased insulinogenesis in manganese-deficient rats. Decreased insulin mRNA levels. FEBS Lett. 1988;239(1):55–8.

    Article  CAS  PubMed  Google Scholar 

  • Baly DL, Schneiderman JS, Garcia-Welsh AL. Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr. 1990;120(9):1075–9.

    CAS  PubMed  Google Scholar 

  • Bandmann O, Weiss K, Kaler SG. Wilson’s disease and other neurological copper disorders. The Lancet Neurology. 2015;14(1):103–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bano D, Zanetti F, Mende Y, Nicotera P. Neurodegenerative processes in Huntington’s disease. Cell Death Dis. 2011;2(11)

    Google Scholar 

  • Bassil F, Fernagut P-O, Bezard E, Meissner WG. Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol. 2014;118:1–18.

    Article  CAS  PubMed  Google Scholar 

  • Bates G, Tabrizi S and Jones L (2014). Huntington’s disease. Huntington’s disease.

    Google Scholar 

  • Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ and Tabrizi SJ (2015). Huntington disease. Nature reviews Disease primers. 1: 15005.

    Google Scholar 

  • Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14(5):329–41.

    Article  CAS  PubMed  Google Scholar 

  • Behrend L, Mohr A, Dick T, Zwacka RM. Manganese superoxide dismutase induces p53-dependent senescence in colorectal cancer cells. Mol Cell Biol. 2005;25(17):7758–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernhard FP, Heinzel S, Binder G, Weber K, Apel A, Roeben B, Deuschle C, Maechtel M, Heger T, Nussbaum S, Gasser T, Maetzler W, Berg D. Insulin-like growth factor 1 (IGF-1) in Parkinson’s disease: potential as trait-, progression- and prediction marker and confounding factors. PLoS One. 2016;11(3)

    Google Scholar 

  • Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, Martin M, Li J, Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ. Axon-glia interactions and the domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin. Neuron. 2001;30(2):369–83.

    Article  CAS  PubMed  Google Scholar 

  • Bilic E, Bilic E, Rudan I, Kusec V, Zurak N, Delimar D, Zagar M. Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol. 2006;13(12):1340–5.

    Article  CAS  PubMed  Google Scholar 

  • Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, Sendtner M, Timmusk T, Lutz B, Galve-Roperh I, Guzmán M. The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 2015;22(10):1618–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, Silani V, Vos PE, Wokke JH, Dobbins T. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I study group. Neurology. 1998;51(2):583–6.

    Article  CAS  PubMed  Google Scholar 

  • Bowman AB, Kwakye GF, Hernández E, Aschner M. Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol. 2011;25(4):191–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci. 2005;6(12):919–30.

    Article  CAS  PubMed  Google Scholar 

  • Cersosimo MG, Koller WC. The diagnosis of manganese-induced parkinsonism. Neurotoxicology. 2005;27(3):340–6.

    Article  PubMed  CAS  Google Scholar 

  • Chan DW, Son SC, Block W, Ye R, Khanna KK, Wold MS, Douglas P, Goodarzi AA, Pelley J, Taya Y, Lavin MF, Lees-Miller SP. Purification and characterization of ATM from human placenta. A manganese-dependent, wortmannin-sensitive serine/threonine protein kinase. J Biol Chem. 2000;275(11):7803–10.

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Zhang X, Song L, Le W. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 2012;22(1):110–6.

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MM, Bowman AB, Aschner M. Manganese homeostasis in the nervous system. J Neurochem. 2015;134(4):601–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ching J, Luebbert SH, Zhang Z, Marupudi N, Banerjee S, Hurd R, Collins IV, Roy L, Ralston L and Fisher JS (2009). Ataxia telangiectasia mutated (ATM) is required in insulin-like growth factor-1 (IGF-1) signaling through the PI3K/Akt pathway. FASEB J. 23.

    Google Scholar 

  • Chinta SJ, Mallajosyula JK, Rane A, Andersen JK. Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett. 2010;486(3):235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chitnis MM, Lodhia KA, Aleksic T, Gao S, Protheroe AS, Macaulay VM. IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination. Oncogene. 2014;33(45):5262–73.

    Article  CAS  PubMed  Google Scholar 

  • Chiu S-L, Chen C-M, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chui D, Yang H, Wang H, Tuo JI, Yu J, Zhang S, Chen Z, Xiao W. The dishomeostasis of metal ions plays an important role for the cognitive impartment. Mol Neurodegener. 2013;8(S1):1–1.

    Google Scholar 

  • Ciucci F, Putignano E, Baroncelli L, Landi S, Berardi N, Maffei L. Insulin-like growth factor 1 (IGF-1) mediates the effects of enriched environment (EE) on visual cortical development. PLoS One. 2007;2(5)

    Google Scholar 

  • Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. The influence of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat. Proc Soc Exp Biol Med Soc Exper Biol Med NY. 1998;219(1):41–7.

    Article  CAS  Google Scholar 

  • Clemmons DR, Busby WH, Arai T, Nam TJ, Clarke JB, Jones JI, Ankrapp DK. Role of insulin-like growth factor binding proteins in the control of IGF actions. Prog Growth Factor Res. 1995;6(2–4):357–66.

    Article  CAS  PubMed  Google Scholar 

  • Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A. Reduced IGF-1 signaling delays age-associated Proteotoxicity in mice. Cell. 2009;139(6):1157–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen E, Du D, Joyce D, Kapernick EA, Volovik Y, Kelly JW, Dillin A. Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection. Aging Cell. 2010;9(2):126–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cordova FM, Aguiar AS, Peres TV, Lopes MW, Gonçalves FM, Remor AP, Lopes SC, Pilati C, Latini AS, Prediger RD, Erikson KM, Aschner M, Leal RB. In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS One. 2012;7(3)

    Google Scholar 

  • Cordova FM, Aguiar AS, Peres TV, Lopes MW, Gonçalves FM, Pedro DZ, Lopes SC, Pilati C, Prediger RD, Farina M, Erikson KM, Aschner M, Leal RB. Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. Arch Toxicol. 2013;87(7):1231–44.

    Article  CAS  PubMed  Google Scholar 

  • Cortes CJ, Spada AR. The many faces of autophagy dysfunction in Huntington’s disease: from mechanism to therapy. Drug Discov Today. 2014;19(7):963–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. The Lancet Neurology. 2004;3(3):169–78.

    Article  CAS  PubMed  Google Scholar 

  • Crittenden PL, Filipov NM. Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells. Journal of applied toxicology : JAT. 2011;31(1):1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuervo A, Zhang S. Selective autophagy and huntingtin: learning from disease. Cell Cycle. 2015;14(11)

    Google Scholar 

  • D’Antonio EL, Hai Y, Christianson DW. Structure and function of non-native metal clusters in human arginase I. Biochemistry. 2012;51(42):8399–409.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G. The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol. 1996;13(3):227–55.

    Article  PubMed  Google Scholar 

  • D’Ercole JA, Ye P, O’Kusky JR. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides. 2002;36(2–3):209–20.

    Article  PubMed  CAS  Google Scholar 

  • Damiano M, Galvan L, Déglon N, Brouillet E. Mitochondria in Huntington’s disease. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2010;1802(1):52–61.

    Article  CAS  Google Scholar 

  • Dearth RK, Hiney JK, Srivastava VK, Hamilton AM, Dees WL. Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats. Exp Biol Med. 2014;239(7):871–82.

    Article  CAS  Google Scholar 

  • Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: the PINK1-parkin link. Biochim Biophys Acta. 2010;1813(4):623–33.

    Article  PubMed  CAS  Google Scholar 

  • Deijen JB, de Boer H, van der Veen EA. Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology. 1998;23(1):45–55.

    Article  CAS  PubMed  Google Scholar 

  • Dentremont KD, Ye P, D’Ercole AJ, O’Kusky JR. Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. Brain Res Dev Brain Res. 1999;114(1):135–41.

    Article  CAS  PubMed  Google Scholar 

  • DeWitt MR, Chen P, Aschner M. Manganese efflux in parkinsonism: insights from newly characterized SLC30A10 mutations. Biochem Biophys Res Commun. 2013;432(1):1–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhamoon MS, Noble JM, Craft S. Intranasal insulin improves cognition and modulates -amyloid in early ad. Neurology. 2009;72(3):292–4.

    Article  PubMed  Google Scholar 

  • Dieter HH, Bayer TA, Multhaup G. Environmental copper and manganese in the pathophysiology of neurologic diseases (Alzheimer’s disease and Manganism). Acta Hydrochim Hydrobiol. 2005;33(1):72–8.

    Article  CAS  Google Scholar 

  • Dormond O, Ponsonnet L, Hasmim M, Foletti A, Rüegg C. Manganese-induced integrin affinity maturation promotes recruitment of alpha V beta 3 integrin to focal adhesions in endothelial cells: evidence for a role of phosphatidylinositol 3-kinase and Src. Thromb Haemost. 2004;92(1):151–61.

    CAS  PubMed  Google Scholar 

  • Duarte AI, Petit GH, Ranganathan S, Li JY, Oliveira CR, Brundin P, Björkqvist M, Rego AC. IGF-1 protects against diabetic features in an in vivo model of Huntington’s disease. Exp Neurol. 2011;231(2):314–9.

    Article  CAS  PubMed  Google Scholar 

  • Ehlayel M, Soliman A, Sanctis V. Linear growth and endocrine function in children with ataxia telangiectasia. Ind J Endocrinol Metabol. 2014;18(7):93–6.

    Article  CAS  Google Scholar 

  • Ekmekcioglu C, Prohaska C, Pomazal K, Steffan I, Schernthaner G, Marktl W. Concentrations of seven trace elements in different hematological matrices in patients with type 2 diabetes as compared to healthy controls. Biol Trace Elem Res. 2001;79(3):205–19.

    Article  CAS  PubMed  Google Scholar 

  • Exil V, Ping L, Yu Y, Chakraborty S, Caito SW, Wells KS, Karki P, Lee E, Aschner M. Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures. PLoS One. 2014;9(5)

    Google Scholar 

  • Farrer LA. Diabetes mellitus in Huntington disease. Clin Genet. 1985;27(1):62–7.

    Article  CAS  PubMed  Google Scholar 

  • Fernandez AM, Torres-Alemán I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci. 2012;13(4):225–39.

    Article  CAS  PubMed  Google Scholar 

  • Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci Off J Soc Neurosci. 2000;20(12):4389–97.

    CAS  Google Scholar 

  • Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal FM. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci Off J Soc Neurosci. 2002;22(5):1592–9.

    CAS  Google Scholar 

  • Ferreira IL, Nascimento MV, Ribeiro M, Almeida S, Cardoso SM, Grazina M, Pratas J, Santos M, Januário C, Oliveira CR and Rego CA (2010). Mitochondrial-dependent apoptosis in Huntington’s disease human cybrids. Exp Neurol 222 (2): 243–255.

    Google Scholar 

  • Ferreira LI, Cunha-Oliveira T, Nascimento MV, Ribeiro M, Proença TM, Januário C, Oliveira CR, Rego CA. Bioenergetic dysfunction in Huntington’s disease human cybrids. Exp Neurol. 2011;231(1):127–34.

    Article  CAS  PubMed  Google Scholar 

  • Filosto M, Scarpelli M, Cotelli M, Vielmi V, Todeschini A, Gregorelli V, Tonin P, Tomelleri G, Padovani A. The role of mitochondria in neurodegenerative diseases. J Neurol. 2011;258(10):1763–74.

    Article  CAS  PubMed  Google Scholar 

  • Freude S, Schilbach K, Schubert M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer’s disease: from model organisms to human disease. Curr Alzheimer Res. 2009;6(3):213–23.

    Article  CAS  PubMed  Google Scholar 

  • Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN. Energy balance in early-stage Huntington disease. Am J Clin Nutr. 2005;81(6):1335–41.

    CAS  PubMed  Google Scholar 

  • Gal J, Ström AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem. 2009;111(4):1062–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci. 2003;26(8):404–6.

    Article  CAS  PubMed  Google Scholar 

  • Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, Mey J, MacDonald ME, Leßmann V, Humbert S, Saudou F. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004;118(1):127–38.

    Article  CAS  PubMed  Google Scholar 

  • Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31.

    Article  CAS  PubMed  Google Scholar 

  • Gelman A, Rawet-Slobodkin M, Elazar Z. Huntingtin facilitates selective autophagy. Nat Cell Biol. 2015;17(3):214–5.

    Article  PubMed  CAS  Google Scholar 

  • Gines S, Ivanova E, Seong I-S, Saura CA, MacDonald ME. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington’s disease knock-in striatal cells. J Biol Chem. 2003;278(50):50514–22.

    Article  CAS  PubMed  Google Scholar 

  • Godau J, Herfurth M, Kattner B, Gasser T, Berg D. Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81(5):536–8.

    Article  PubMed  Google Scholar 

  • Goetz EM, Shankar B, Zou Y, Morales JC, Luo X, Araki S, Bachoo R, Mayo LD, Boothman DA. ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. Oncogene. 2011;30(35):3745–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomes C, Escrevente C, Costa J. Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett. 2010;475(3):145–9.

    Article  CAS  PubMed  Google Scholar 

  • Gong L, Zhang QL, Zhang N, Hua WY, Huang YX, Di PW, Huang T, Xu XS, Liu CF, Hu LF, Luo WF. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem. 2012;123(5):876–85.

    Article  CAS  PubMed  Google Scholar 

  • Goodman A, Murgatroyd PR, Medina-Gomez G, Wood NI, Finer N, Vidal-Puig AJ, Morton JA, Barker RA. The metabolic profile of early Huntington’s disease- a combined human and transgenic mouse study. Exp Neurol. 2008;210(2):691–8.

    Article  CAS  PubMed  Google Scholar 

  • Gorojod RM, Alaimo A, Porte Alcon S, Pomilio C, Saravia F, Kotler ML. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions. Free Radic Biol Med. 2015;87:237–51.

    Article  CAS  PubMed  Google Scholar 

  • Gouarné C, Tardif G, Tracz J, Latyszenok V, Michaud M, Clemens L, Yu-Taeger L, Nguyen H, Bordet T, Pruss RM. Early deficits in glycolysis are specific to striatal neurons from a rat model of Huntington disease. PLoS One. 2013;8(11)

    Google Scholar 

  • Greenwood BN, Fleshner M. Exercise, learned helplessness, and the stress-resistant brain. NeuroMolecular Med. 2008;10(2):81–98.

    Article  CAS  PubMed  Google Scholar 

  • Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P, O’Connor R, O’Neill C. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology. J Neurochem. 2005;93(1):105–17.

    Article  CAS  PubMed  Google Scholar 

  • Guilarte TR. APLP1, Alzheimer’s-like pathology and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Neurotoxicology. 2010a;31(5):572–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guilarte TR. Manganese and Parkinson’s disease: a critical review and new findings. Environ Health Perspect. 2010b;118(8):1071–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guilarte TR, Gonzales KK. Manganese-induced parkinsonism is not idiopathic Parkinson’s disease: environmental and genetic evidence. Toxicol Sci. 2015;146(2):204–12.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gunter TE, Gavin CE, Gunter KK. The case for manganese interaction with mitochondria. Neurotoxicology. 2009;30(4):727–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gusella JF, MacDonald ME. Huntington’s disease: the case for genetic modifiers. Genome Med. 2009;1(8):80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Haj-ali V, Mohaddes G, Babri SH. Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behav Neurosci. 2009;123(6):1309.

    Article  CAS  PubMed  Google Scholar 

  • Halaby M-J, Hibma JC, He J, Yang D-Q. ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. Cell Signal. 2008;20(8):1555–63.

    Article  CAS  PubMed  Google Scholar 

  • Hare DJ, Faux NG, Roberts BR, Volitakis I, Martins RN, Bush AI. Lead and manganese levels in serum and erythrocytes in Alzheimer’s disease and mild cognitive impairment: results from the Australian imaging, biomarkers and lifestyle flagship study of ageing. Metallomics. 2016;8(6):628–32.

    Article  CAS  PubMed  Google Scholar 

  • Harischandra DS, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG. α-Synuclein protects against manganese neurotoxic insult during the early stages of exposure in a dopaminergic cell model of Parkinson’s disease. Toxicol Sci. 2015;143(2):454–68.

    Article  CAS  PubMed  Google Scholar 

  • Harris H, Rubinsztein DC. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol. 2011;8(2):108–17.

    Article  PubMed  CAS  Google Scholar 

  • Hiney JK, Srivastava VK, Dees WL. Manganese induces IGF-1 and cyclooxygenase-2 gene expressions in the basal hypothalamus during prepubertal female development. Toxicol Sci Off J Soc Toxicol. 2011;121(2):389–96.

    Article  CAS  Google Scholar 

  • Ho C-mJ, Zheng S, Comhair SA, Farver C, Erzurum SC. Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cancer Res. 2001;61(23):8578–85.

    CAS  Google Scholar 

  • Hodge RD, D’Ercole JA, O’Kusky JR. Insulin-like growth factor-I accelerates the cell cycle by decreasing G1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci Off J Soc Neurosci. 2004;24(45):10201–10.

    Article  CAS  Google Scholar 

  • Hölscher C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimer’s Dementia J Alzheimer’s Assoc. 2014;10(1 Suppl):7.

    Google Scholar 

  • Homolak J, Janeš I, Filipović M. The role of IGF-1 in neurodegenerative diseases. Gyrus. 2015;3(3):162–7.

    Article  Google Scholar 

  • Horning KJ, Caito SW, Tipps KG, Bowman AB, Aschner M. Manganese is essential for neuronal health. Annu Rev Nutr. 2015;35:71–108.

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Rosen DG, Zhou Y, Feng L, Yang G, Liu J, Huang P. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem. 2005;280(47):39485–92.

    Article  CAS  PubMed  Google Scholar 

  • Humbert S, Saudou F. Huntingtin phosphorylation and signaling pathways that regulate toxicity in Huntington’s disease. Clin Neurosci Res. 2003;3(3):149–55.

    Article  CAS  Google Scholar 

  • Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F. The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves huntingtin phosphorylation by Akt. Dev Cell. 2002;2(6):831–7.

    Article  CAS  PubMed  Google Scholar 

  • Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR. Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes. Diabetes. 1999;48(3):649–51.

    Article  CAS  PubMed  Google Scholar 

  • Hurtado-Chong A, Yusta-Boyo MJ, Vergaño-Vera E, Bulfone A, Pablo F, Vicario-Abejón C. IGF-I promotes neuronal migration and positioning in the olfactory bulb and the exit of neuroblasts from the subventricular zone. Eur J Neurosci. 2009;30(5):742–55.

    Article  PubMed  Google Scholar 

  • Ismailoglu I, Chen Q, Popowski M, Yang L, Gross SS, Brivanlou AH. Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol. 2014;391(2):230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang B-CC. Induction of COX-2 in human airway cells by manganese: role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion. Toxicology in vitro : an international journal published in association with BIBRA. 2009;23(1):120–6.

    Article  CAS  Google Scholar 

  • Jiu Y-M, Yue Y, Yang S, Liu L, Yu J-W, Wu Z-X, Xu T. Insulin-like signaling pathway functions in integrative response to an olfactory and a gustatory stimuli in Caenorhabditis elegans. Protein Cell. 2010;1(1):75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johansson P, Åberg D, Johansson J-O, Mattsson N, Hansson O, Ahrén B, Isgaard J, Åberg DN, Blennow K, Zetterberg H, Wallin A, Svensson J. Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer’s disease. Psychoneuroendocrinology. 2013;38(9):1729–37.

    Article  CAS  PubMed  Google Scholar 

  • Johri A, Beal FM. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012;342(3):619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Josefsen K, Nielsen MD, Jørgensen KH, Bock T, Nørremølle A, Sørensen SA, Naver B, Hasholt L. Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington’s disease. J Neuroendocrinol. 2007;20(2):165–72.

    Article  PubMed  CAS  Google Scholar 

  • Kalia K, Jiang W, Zheng W. Manganese accumulates primarily in nuclei of cultured brain cells. Neurotoxicology. 2008;29(3):466–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. Structure of a unique binuclear manganese cluster in arginase. Nature. 1996;383(6600):554–7.

    Article  CAS  PubMed  Google Scholar 

  • Keen CL, Baly DL, Lönnerdal B. Metabolic effects of high doses of manganese in rats. Biol Trace Elem Res. 1984;6(4):309–15.

    Article  CAS  PubMed  Google Scholar 

  • Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho S, Schubert R, Zielen S. Extracerebellar MRI—lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010;9(2):190–7.

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal FM, Ferrante RJ. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet. 2010;19(20):3919–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh ES, Kim SJ, Yoon HE, Chung JH, Chung S, Park CW, Chang YS, Shin SJ. Association of blood manganese level with diabetes and renal dysfunction: a cross-sectional study of the Korean general population. BMC Endocrine Disorders. 2014;14:24.

    Article  PubMed  PubMed Central  Google Scholar 

  • Koroshetz WJ, Jenkins BG, Rosen BR, Beal FM. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol. 1997;41(2):160–5.

    Article  CAS  PubMed  Google Scholar 

  • Krishnamurthi R, Stott S, Maingay M, Faull RLM, McCarthy D, Gluckman P, Guan J. N-terminal tripeptide of IGF-1 improves functional deficits after 6-OHDA lesion in rats. Neuroreport. 2004;15(10):1601–4.

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Singh S, Kumar V, Kumar D, Agarwal S, Rana M. Huntington’s disease: an update of therapeutic strategies. Gene. 2015;556(2):91–7.

    Article  CAS  PubMed  Google Scholar 

  • Kwakye GF, Li D, Bowman AB. Novel high-throughput assay to assess cellular manganese levels in a striatal cell line model of Huntington’s disease confirms a deficit in manganese accumulation. Neurotoxicology. 2011;32(5):630–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M. Manganese-induced parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health. 2015;12(7):7519–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lalić NM, Marić J, Svetel M, Jotić A, Stefanova E, Lalić K, Dragašević N, Miličić T, Lukić L, Kostić VS. Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol. 2008;65(4):476–80.

    Article  PubMed  Google Scholar 

  • Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. EMBO Rep. 2004;5(10):958–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larsen NA, Pakkenberg H, Damsgaard E, Heydorn K. Topographical distribution of arsenic, manganese, and selenium in the normal human brain. J Neurol Sci. 1979;42(3):407–16.

    Article  CAS  PubMed  Google Scholar 

  • Lee B, Pine M, Johnson L, Rettori V, Hiney JK, Dees LW. Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats. Reproductive toxicology (Elmsford, NY). 2006;22(4):580–5.

    Article  CAS  Google Scholar 

  • Lee B, Hiney JK, Pine MD, Srivastava VK, Dees LW. Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action. J Physiol. 2007;578(3):765–72.

    Article  CAS  PubMed  Google Scholar 

  • Lee S-H, Jouihan HA, Cooksey RC, Jones D, Kim HJ, Winge DR, McClain DA. Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion. Endocrinology. 2013;154(3):1029–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JH, Tecedor L, Chen Y, Monteys A, Sowada MJ, Thompson LM, Davidson BL. Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron. 2014;85(2):303–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci. 2014;34(42):14079–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lim J, Yue Z. Neuronal aggregates: formation, clearance, and spreading. Dev Cell. 2015;32(4):491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liou J-C, Tsai F-Z, Ho S-Y. Potentiation of quantal secretion by insulin-like growth factor-1 at developing motoneurons in Xenopus cell culture. J Physiol. 2003;553(Pt 3):719–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu W, Ye P, O’Kusky JR, D’Ercole JA. Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. J Neurosci Res. 2009;87(13):2821–32.

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225(1):54–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopes C, Ribeiro M, Duarte AI, Humbert S, Saudou F, Pereira de Almeida L, Hayden M, Rego AC. IGF-1 intranasal administration rescues Huntington’s disease phenotypes in YAC128 mice. Mol Neurobiol. 2014;49(3):1126–42.

    Article  CAS  PubMed  Google Scholar 

  • Lou S, Lepak T, Eberly LE, Roth B, Cui W, Zhu X-H, Öz G, Dubinsky JM. Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress. Human Mol Genet. 2016;

    Google Scholar 

  • Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA. ATM regulates insulin-like growth factor 1-secretory Clusterin (IGF-1-sCLU) expression that protects cells against senescence. PLoS One. 2014;9(6)

    Google Scholar 

  • Ma J, Jiang Q, Xu J, Sun Q, Qiao Y, Chen W, Wu Y, Wang Y, Xiao Q, Liu J, Tang H, Chen S. Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson’s disease. Dement Geriatr Cogn Disord. 2015;39(5–6):251–6.

    Article  CAS  PubMed  Google Scholar 

  • Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci. 2009;29(20):6734–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin LJ. Chapter 11 biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci. 2012;107:355–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin WWR, Wieler M, Hanstock CC. Is brain lactate increased in Huntington’s disease? J Neurol Sci. 2007;263(1–2):70–4.

    Article  CAS  PubMed  Google Scholar 

  • Martin DDO, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 2014;38(1):26–35.

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R, Arias E, Harris S, Sulzer D, Cuervo A. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci. 2010;13(5):567–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maydan M, McDonald PC, Sanghera J, Yan J, Rallis C, Pinchin S, Hannigan GE, Foster LJ, Ish-Horowicz D, Walsh MP, Dedhar S. Integrin-linked kinase is a functional Mn2+−dependent protein kinase that regulates glycogen synthase kinase-3β (GSK-3β) phosphorylation. PLoS One. 2010;5(8)

    Google Scholar 

  • Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR, Hayden MR. Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci. 2010;30(43):14318–29.

    Article  CAS  PubMed  Google Scholar 

  • Michiorri S, Gelmetti V, Giarda E, Lombardi F, Romano F, Marongiu R, Nerini-Molteni S, Sale P, Vago R, Arena G, Torosantucci L, Cassina L, Russo MA, Dallapiccola B, Valente EM, Casari G. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ. 2010;17(6):962–74.

    Article  CAS  PubMed  Google Scholar 

  • Milakovic T, Johnson GVW. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem. 2005;280(35):30773–82.

    Article  CAS  PubMed  Google Scholar 

  • Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrinol Metab. 2007;293(1):4.

    Article  CAS  Google Scholar 

  • Miyata S, Nakamura S, Nagata H, Kameyama M. Increased manganese level in spinal cords of amyotrophic lateral sclerosis determined by radiochemical neutron activation analysis. J Neurol Sci. 1983;61(2):283–93.

    Article  CAS  PubMed  Google Scholar 

  • Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A. Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS One. 2007;2(7)

    Google Scholar 

  • Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31

    Google Scholar 

  • de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis. 2005;7

    Google Scholar 

  • Morello M, Canini A, Mattioli P, Sorge RP, Alimonti A, Bocca B, Forte G, Martorana A, Bernardi G, Sancesario G. Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats an electron spectroscopy imaging and electron energy-loss spectroscopy study. Neurotoxicology. 2008;29(1):60–72.

    Article  CAS  PubMed  Google Scholar 

  • Morrison BD, Feltz SM, Pessin JE. Polylysine specifically activates the insulin-dependent insulin receptor protein kinase. J Biol Chem. 1989;264(17):9994–10001.

    CAS  PubMed  Google Scholar 

  • Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K. Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2005;235

    Google Scholar 

  • Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Morita K, Shoji M, Abe K. Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurol Res. 2013;27(7):768–72.

    Article  Google Scholar 

  • Nagata H, Miyata S, Nakamura S, Kameyama M, Katsui Y. Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis. J Neurol Sci. 1985;67(2):173–8.

    Article  CAS  PubMed  Google Scholar 

  • Naia L, Ferreira IL, Cunha-Oliveira T, Duarte AI, Ribeiro M, Rosenstock TR, Laço MNN, Ribeiro MJ, Oliveira CR, Saudou F, Humbert S, Rego AC. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s disease human lymphoblasts. Mol Neurobiol. 2015;51(1):331–48.

    Article  CAS  PubMed  Google Scholar 

  • Naia L, Ribeiro M, Rodrigues J, Duarte AI, Lopes C, Rosenstock TR, Hayden MR and Rego CA (2016). Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides.

    Google Scholar 

  • Nakaso K, Ito S, Nakashima K. Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell death in a Parkinson’s disease model of SH-SY5Y cells. Neurosci Lett. 2008;432

    Google Scholar 

  • Narendra D, Tanaka A, Suen D-F, Youle RJ. Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy. 2009;5(5):706–8.

    Article  CAS  PubMed  Google Scholar 

  • Neill C. PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol. 2013;48(7):647–53.

    Article  CAS  Google Scholar 

  • Neulen A, Blaudeck N, Zittrich S, Metzler D, Pfitzer G, Stehle R. Mn2+−dependent protein phosphatase 1 enhances protein kinase A-induced Ca2+ desensitisation in skinned murine myocardium. Cardiovasc Res. 2007;74(1):124–32.

    Article  CAS  PubMed  Google Scholar 

  • Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort. Pediatr Res. 2016;79(6):889–94.

    Article  CAS  PubMed  Google Scholar 

  • O’Kusky JR, Ye P, D’Ercole AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci Off J Soc Neurosci. 2000;20(22):8435–42.

    Google Scholar 

  • Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh LJ, Housman DE, Thompson LM, Steffan JS. Potential function for the huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci. 2014;111(47):16889–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Offen D, Shtaif B, Hadad D, Weizman A, Melamed E, Gil-Ad I. Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson’s disease. Neurosci Lett. 2001;316(3):129–32.

    Article  CAS  PubMed  Google Scholar 

  • Oishi K, Watatani K, Itoh Y, Okano H, Guillemot F, Nakajima K, Gotoh Y. Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1. Proc Natl Acad Sci. 2009;106(31):13064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oláh J, Klivényi P, Gardián G, Vécsei L, Orosz F, Kovacs GG, Westerhoff HV, Ovádi J. Increased glucose metabolism and ATP level in brain tissue of Huntington’s disease transgenic mice. FEBS J. 2008;275(19):4740–55.

    Article  PubMed  CAS  Google Scholar 

  • Ozdinler HP, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006;9(11):1371–81.

    Article  PubMed  CAS  Google Scholar 

  • Paull TT, Gellert M. The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell. 1998;1(7):969–79.

    Article  CAS  PubMed  Google Scholar 

  • Peres T, Parmalee NL, Martinez-Finley EJ, Aschner M. Untangling the manganese-α-Synuclein web. Front Neurosci. 2016;10:364.

    Article  PubMed  PubMed Central  Google Scholar 

  • Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci. 2001;98(4):1676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peters TL, Beard JD, Umbach DM, Allen K, Keller J, Mariosa D, Sandler DP, Schmidt S, Fang F, Ye W, Kamel F. Blood levels of trace metals and amyotrophic lateral sclerosis. Neurotoxicology. 2016;54:119–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Picillo M, Erro R, Santangelo G, Pivonello R, Longo K, Pivonello C, Vitale C, Amboni M, Moccia M, Colao A, Barone P, Pellecchia M. Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson’s disease. J Neurol. 2013;260(7):1724–30.

    Article  CAS  PubMed  Google Scholar 

  • Podolsky S, Leopold N, Sax D. Increased frequency of diabetes mellitus in patients with Huntington’s chorea. Lancet. 1972;299(7765):1356–9.

    Article  Google Scholar 

  • Pouladi MA, Xie Y, Skotte NH, Ehrnhoefer DE, Graham RK, Kim JE, Bissada N, Yang XW, Paganetti P, Friedlander RM, Leavitt BR, Hayden MR. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet. 2010;19(8):1528–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prohaska JR. Functions of trace elements in brain metabolism. Physiol Rev. 1987;67(3):858–901.

    CAS  PubMed  Google Scholar 

  • Pryor WM, Biagioli M, Shahani N, Swarnkar S, Huang W-C, Page DT, MacDonald ME, Subramaniam S. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Sci Signal. 2014;7(349)

    Google Scholar 

  • Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, Severijnen L-A, Di Toro ML, Mignarri A, Monti L, Sanna A, Lu P, Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP, Bonifati V. Mutations in SLC30A10 cause parkinsonism and dystonia with Hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90(3):467–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quesada A, Lee BY, Micevych PE. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson’s disease. Dev Neurobiol. 2008;68(5):632–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rauskolb S, Dombert B, Sendtner M. Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis. Neurobiol Dis. 2016;

    Google Scholar 

  • Ravikumar B, Rubinsztein DC. Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? Mol Asp Med. 2006;27(5–6):520–7.

    Article  CAS  Google Scholar 

  • Reddy HP, Mao P, Manczak M. Mitochondrial structural and functional dynamics in Huntington’s disease. Brain Res Rev. 2009;61(1):33–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JCS, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2007;70(6):440–8.

    Article  PubMed  Google Scholar 

  • Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984;63(3):317–24.

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC. Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radic Biol Med. 2014;74:129–44.

    Article  CAS  PubMed  Google Scholar 

  • Rickle A, Bogdanovic N, Volkman I, Winblad B, Ravid R, Cowburn RF. Akt activity in Alzheimer’s disease and other neurodegenerative disorders. Neuroreport. 2004;15(6):955–9.

    Article  CAS  PubMed  Google Scholar 

  • Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8

    Google Scholar 

  • Roos PM, Lierhagen S, Flaten T, Syversen T, Vesterberg O, Nordberg M. Manganese in cerebrospinal fluid and blood plasma of patients with amyotrophic lateral sclerosis. Exp Biol Med. 2012;237(7):803–10.

    Article  CAS  Google Scholar 

  • Root CM, Ko KI, Jafari A, Wang JW. Presynaptic facilitation by neuropeptide signaling mediates odor-driven food search. Cell. 2011;145(1):133–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubenstein AH, Levin NW, Elliott GA. Manganese-induced hypoglycaemia. Lancet (London, England). 1962;2(7270):1348–51.

    Article  CAS  Google Scholar 

  • Rui Y-NN XZ, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ, Cuervo AM, Zhang S. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015;17(3)

    Google Scholar 

  • Saavedra A, García-Martínez JM, Xifró X, Giralt A, Torres-Peraza JF, Canals JM, Díaz-Hernández M, Lucas JJ, Alberch J, Pérez-Navarro E. PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death Differ. 2009;17(2):324–35.

    Article  PubMed  CAS  Google Scholar 

  • Saccà F, Quarantelli M, Rinaldi C, Tucci T, Piro R, Perrotta G, Carotenuto B, Marsili A, Palma V, Michele G, Brunetti A, Morra V, Filla A, Salvatore M. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol. 2012;259(1):132–8.

    Article  PubMed  CAS  Google Scholar 

  • Saleh N, Moutereau S, Durr A, Krystkowiak P, Azulay J-P, Tranchant C, Broussolle E, Morin F, Bachoud-Lévi A-C, Maison P. Neuroendocrine disturbances in Huntington’s disease. PLoS One. 2009;4(3)

    Google Scholar 

  • Saleh N, Moutereau S, Azulay JP, Verny C, Simonin C, Tranchant C, Hawajri EN, Bachoud-Lévi AC, Maison P, Group H. High insulinlike growth factor I is associated with cognitive decline in Huntington disease. Neurology. 2010;75(1):57–63.

    Article  CAS  PubMed  Google Scholar 

  • Sarkar S, Rubinsztein DC. Huntington’s disease: degradation of mutant huntingtin by autophagy. FEBS J. 2008;275(17):4263–70.

    Article  CAS  PubMed  Google Scholar 

  • Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 2008;16(1):46–56.

    Article  PubMed  CAS  Google Scholar 

  • Sasazawa Y, Sato N, Umezawa K, Simizu S. Conophylline protects cells in cellular models of neurodegenerative diseases by inducing mammalian target of rapamycin (mTOR)-independent autophagy. J Biol Chem. 2015;290(10):6168–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284(19):12783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saudou F, Humbert S. The biology of huntingtin. Neuron. 2016;89(5):910–26.

    Article  CAS  PubMed  Google Scholar 

  • Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci Lett. 2001;315(3):149–53.

    Article  CAS  PubMed  Google Scholar 

  • Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Küstermann E. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Nat Acad Sci USA. 2004:101.

    Google Scholar 

  • Schubert R, Reichenbach J, Zielen S. Growth factor deficiency in patients with ataxia telangiectasia. Clinical & Experimental Immunology. 2005;140(3):517–9.

    Article  CAS  Google Scholar 

  • Shahrabani-Gargir L, Pandita TK, Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004;145(12):5679–87.

    Article  CAS  PubMed  Google Scholar 

  • Shen F, Cai W-S, Li J-L, Feng Z, Cao J, Xu B. The association between deficient manganese levels and breast cancer: a meta-analysis. Int J Clin Exp Med. 2015;8(3):3671–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MV. Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci U S A. 2001;98(6):3561–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sørensen AS, Fenger K, Olsen JH. Significantly lower incidence of cancer among patients with Huntington disease. Cancer. 1999;86(7):1342–6.

    Article  PubMed  Google Scholar 

  • Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. 2008;71(22):1770–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Cáceres A, Pfenninger KH, Quiroga S. IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci. 2006;9(8):993–5.

    Article  CAS  PubMed  Google Scholar 

  • Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;5(4)

    Google Scholar 

  • Srivastava VK, Hiney JK, Dees LW. Prepubertal ethanol exposure alters hypothalamic transforming growth factor-α and erbB1 receptor signaling in the female rat. Alcohol. 2011;45(2):173–81.

    Article  CAS  PubMed  Google Scholar 

  • Srivastava VK, Hiney JK, Dees WL. Early life manganese exposure upregulates tumor-associated genes in the hypothalamus of female rats: relationship to manganese-induced precocious puberty. Toxicol Sci. 2013;136(2):373–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava VK, Hiney JK, Dees WL. Manganese stimulated Kisspeptin is mediated by the insulin-like growth factor-1/Akt/ mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology. 2016;

    Google Scholar 

  • Stansfield KH, Bichell T, Bowman AB, Guilarte TR. BDNF and huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity. J Neurochem. 2014;131(5):655–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu JX, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimer’s Dis. 2005;7

    Google Scholar 

  • Subasinghe S, Greenbaum AL, McLean P. The insulin-mimetic action of Mn2+: involvement of cyclic nucleotides and insulin in the regulation of hepatic hexokinase and glucokinase. Biochem Med. 1985;34(1):83–92.

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci. 2007;30(5):244–50.

    Article  CAS  PubMed  Google Scholar 

  • Suzanne M, Wands JR. Alzheimer’s disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol. 2008;2

    Google Scholar 

  • Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AHV, Warner TT. Creatine therapy for Huntington’s disease: clinical and MRS findings in a 1-year pilot study. Neurology. 2003;61(1):141–2.

    Article  CAS  PubMed  Google Scholar 

  • Takeda A. Manganese action in brain function. Brain Res Rev. 2003;41(1):79–87.

    Article  CAS  PubMed  Google Scholar 

  • Tidball AM, Bryan MR, Uhouse MA, Kumar KK, Aboud AA, Feist JE, Ess KC, Neely DM, Aschner M, Bowman AB. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington’s disease. Hum Mol Genet. 2015a;24(7):1929–44.

    Article  CAS  PubMed  Google Scholar 

  • Tidball AM, Bichell T, Bowman AB. Manganese in health and disease. rsc. 2015b:540–73.

    Google Scholar 

  • Timmons S, Coakley MF, Moloney AM, Neill C. Akt signal transduction dysfunction in Parkinson’s disease. Neurosci Lett. 2009;467(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  • Tong M, Dong M, de la Monte SM. Brain insulin-like growth factor and neurotrophin resistance in Parkinson’s disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimer’s Dis JAD. 2009;16(3):585–99.

    Article  CAS  PubMed  Google Scholar 

  • Torres-Aleman I. Targeting insulin-like growth factor-1 to treat Alzheimer’s disease. Expert Opin Ther Targets. 2007;11(12):1535–42.

    Article  CAS  PubMed  Google Scholar 

  • Trejo JL, Llorens-Martín MV, Torres-Alemán I. The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci. 2007;37(2):402–11.

    Article  PubMed  CAS  Google Scholar 

  • Truant R, Atwal R, Desmond C, Munsie L, Tran T. Huntington’s disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases. FEBS J. 2008;275(17):4252–62.

    Article  CAS  PubMed  Google Scholar 

  • Trujillo KM, Yuan SS, Lee EY, Sung P. Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem. 1998;273(34):21447–50.

    Article  CAS  PubMed  Google Scholar 

  • Valenciano A, Henríquez-Hernández L, Moreno M, Lloret M, Lara P. Role of IGF-1 receptor in radiation response. Transl Oncol. 2014;5(1):1–9.

    Article  Google Scholar 

  • Vara J, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.

    Article  CAS  Google Scholar 

  • Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Leemputte VM, Hespel P, Dom R. Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology. 2003;61(7):925–30.

    Article  CAS  PubMed  Google Scholar 

  • Vidal J-SS, Hanon O, Funalot B, Brunel N, Viollet C, Rigaud A-SS, Seux M-LL, le-Bouc Y, Epelbaum J and Duron E (2016). Low serum insulin-like growth factor-I predicts cognitive decline in Alzheimer’s disease. Journal of Alzheimer’s disease : JAD 52 (2): 641–649.

    Google Scholar 

  • Vives-Bauza C, Przedborski S. Mitophagy: the latest problem for Parkinson’s disease. Trends Mol Med. 2010;17(3):158–65.

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Fan H, Ying Z, Li B, Wang H, Wang G. Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett. 2010;469(1):112–6.

    Article  CAS  PubMed  Google Scholar 

  • Warby SC, Doty CN, Graham RK, Shively J, Singaraja RR, Hayden MR. Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol Cell Neurosci. 2009;40(2):121–7.

    Article  CAS  PubMed  Google Scholar 

  • Wedler FC, Ley BW. Kinetic, ESR, and trapping evidence for in vivo binding of Mn(II) to glutamine synthetase in brain cells. Neurochem Res. 1994;19(2):139–44.

    Article  CAS  PubMed  Google Scholar 

  • Weydert CJ, Waugh TA, Ritchie JM, Iyer KS, Smith JL, Li L, Spitz DR, Oberley LW. Overexpression of manganese or copper-zinc superoxide dismutase inhibits breast cancer growth. Free Radic Biol Med. 2006;41(2):226–37.

    Article  CAS  PubMed  Google Scholar 

  • Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, Spada AR. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1α in Huntington’s disease neurodegeneration. Cell Metab. 2006;4(5):349–62.

    Article  CAS  PubMed  Google Scholar 

  • Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O’Kane CJ, Floto R, Rubinsztein DC. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol. 2008;4(5):295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams BB, Kwakye GF, Wegrzynowicz M, Li D, Aschner M, Erikson KM, Bowman AB. Altered manganese homeostasis and manganese toxicity in a Huntington’s disease striatal cell model are not explained by defects in the iron transport system. Toxicol Sci. 2010a;117(1):169–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams BB, Li D, Wegrzynowicz M, Vadodaria BK, Anderson JG, Kwakye GF, Aschner M, Erikson KM, Bowman AB. Disease-toxicant screen reveals a neuroprotective interaction between Huntington’s disease and manganese exposure. J Neurochem. 2010b;112(1):227–37.

    Article  CAS  PubMed  Google Scholar 

  • Wolfe DM, Lee J, Kumar A, Lee S, Orenstein SJ, Nixon RA. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci. 2013;37(12):1949–61.

    Article  PubMed  PubMed Central  Google Scholar 

  • Woźniak-Celmer E, Ołdziej S, Ciarkowski J. Theoretical models of catalytic domains of protein phosphatases 1 and 2A with Zn2+ and Mn2+ metal dications and putative bioligands in their catalytic centers. Acta Biochim Pol. 2001;48(1):35–52.

    PubMed  Google Scholar 

  • Xiang Y, Ding N, Xing Z, Zhang W, Liu H, Li Z. Insulin-like growth factor-1 regulates neurite outgrowth and neuronal migration from Organotypic cultured dorsal root ganglion. Int J Neurosci. 2010;121(2):101–6.

    Article  PubMed  CAS  Google Scholar 

  • Xing C, Yin Y, He X, Xie Z. Effects of insulin-like growth factor 1 on voltage-gated ion channels in cultured rat hippocampal neurons. Brain Res. 2006;1072(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  • Xing C, Yin Y, Chang R, Gong X, He X, Xie Z. Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neurons. Exp Neurol. 2007;205(1):222–9.

    Article  CAS  PubMed  Google Scholar 

  • Xiromerisiou G, Hadjigeorgiou GM, Papadimitriou A, Katsarogiannis E, Gourbali V, Singleton AB. Association between AKT1 gene and Parkinson’s disease: a protective haplotype. Neurosci Lett. 2008;436

    Google Scholar 

  • Xu B, Bird VG, Miller WT. Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains. J Biol Chem. 1995;270(50):29825–30.

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Liu C, Chen S, Ye Y, Guo M, Ren Q, Liu L, Zhang H, Xu C, Zhou Q. Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cell Signal. 2014;26

    Google Scholar 

  • Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol. 2006;172(5):719–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang D-S, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain J Neurol. 2011;134(Pt 1):258–77.

    Article  Google Scholar 

  • Yu HW, Cuervo A, Kumar A, Peterhoff CM, Schmidt SD, Lee J-H, Mohan PS, Mercken M, Farmery MR, Tjernberg LO. Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol. 2005;171

    Google Scholar 

  • Zala D, Colin E, Rangone H, Liot G, Humbert S, Saudou F. Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet. 2008;17(24):3837–46.

    Article  CAS  PubMed  Google Scholar 

  • Zhang D, Kanthasamy A, Anantharam V, Kanthasamy A. Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line. Toxicol Appl Pharmacol. 2011;254(2):65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Cao R, Cai T, Aschner M, Zhao F, Yao T, Chen Y, Cao Z, Luo W, Chen J. The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. Neurotox Res. 2013;24(4):478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Miah M, Culbreth M, Aschner M. Autophagy in neurodegenerative diseases and metal neurotoxicity. Neurochem Res. 2016;41(1–2):409–22.

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem. 1999;274(49):34893–902.

    Article  CAS  PubMed  Google Scholar 

  • Zhou T, Chou J, Zhou Y, Simpson DA, Cao F, Bushel PR, Paules RS, Kaufmann WK. Ataxia telangiectasia-mutated dependent DNA damage checkpoint functions regulate gene expression in human fibroblasts. Mol Cancer Res MCR. 2007;5(8):813–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Miles R. Bryan & Aaron B. Bowman

  2. Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Miles R. Bryan & Aaron B. Bowman

  3. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Miles R. Bryan & Aaron B. Bowman

  4. Vanderbilt Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Aaron B. Bowman

Authors
  1. Miles R. Bryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron B. Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miles R. Bryan .

Editor information

Editors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Michael Aschner

  2. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA

    Lucio G. Costa

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Bryan, M.R., Bowman, A.B. (2017). Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders. In: Aschner, M., Costa, L. (eds) Neurotoxicity of Metals. Advances in Neurobiology, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-60189-2_6

Download citation

Publish with us

Policies and ethics

Search

Navigation