Abstract
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.
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References
Orr H, Chung M-y, Banfi S, Kwiatkowski Jr TJ, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4:221–6.
Opal P, Zoghbi HY. Diseases of the nervous system. Diseases of the Nervous System. 2002;II:1880-95.
Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30:575–621.
Li X, Li H, Li XJ. Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases. Brain Res Rev. 2008;59(1):245–52.
Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000;3(2):157–63.
Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet. 2004;13(20):2535–43.
Riley BE, Orr HT. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev. 2006;20(16):2183–92.
Cvetanovic M, Kular RK, Opal P. LANP mediates neuritic pathology in Spinocerebellar ataxia type 1. Neurobiol Dis. 2012;48(3):526–32.
Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002;34(6):905–19.
Bonaguidi MA, Peng CY, McGuire T, Falciglia G, Gobeske KT, Czeisler C, et al. Noggin expands neural stem cells in the adult hippocampus. J Neurosci Off J Soc Neurosci. 2008;28(37):9194–204.
Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice. J Neurosci Res. 2010;88(10):2103–17.
Hu YS, Xu P, Pigino G, Brady ST, Larson J, Lazarov O. Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 mice. FASEB J Off Publ Fed Am Soc Exp Biol. 2010;24(6):1667–81.
Meyers EA, Gobeske KT, Bond AM, Jarrett JC, Peng CY, Kessler JA. Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition. Neurobiol Aging. 2016;38:164–75.
Venkatraman A, Hu YS, Didonna A, Cvetanovic M, Krbanjevic A, Bilesimo P, et al. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet. 2014;23(14):3733–45.
Cvetanovic M, Rooney RJ, Garcia JJ, Toporovskaya N, Zoghbi HY, Opal P. The role of LANP and ataxin 1 in E4F-mediated transcriptional repression. EMBO Rep. 2007;8(7):671–7.
Hu YS, Long N, Pigino G, Brady ST, Lazarov O. Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3beta, neurotrophin-3 and CREB signaling. PLoS One. 2013;8(5), e64460.
Kitamura T, Inokuchi K. Role of adult neurogenesis in hippocampal-cortical memory consolidation. Mol Brain. 2014;7:13.
Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132(4):645–60.
Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R, et al. Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med. 2007;4(5), e182.
Cvetanovic M, Patel JM, Marti HH, Kini AR, Opal P. Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med. 2011;17(11):1445–7.
Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, et al. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci. 2005;21(1):1–14.
Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol. 2003;467(1):1–10.
Faigle R, Song H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta. 2013;1830(2):2435–48.
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99(18):11946–50.
Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature. 1990;347(6295):762–5.
Kirschenbaum B, Goldman SA. Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc Natl Acad Sci U S A. 1995;92(1):210–4.
Maric D, Fiorio Pla A, Chang YH, Barker JL. Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors. J Neurosci Off J Soc Neurosci. 2007;27(8):1836–52.
Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci Off J Soc Neurosci. 1999;19(19):8487–97.
Erlandsson A, Brannvall K, Gustafsdottir S, Westermark B, Forsberg-Nilsson K. Autocrine/paracrine platelet-derived growth factor regulates proliferation of neural progenitor cells. Cancer Res. 2006;66(16):8042–8.
Arsenijevic Y, Weiss S, Schneider B, Aebischer P. Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. J Neurosci Off J Soc Neurosci. 2001;21(18):7194–202.
Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C. Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci Off J Soc Neurosci. 2007;27(25):6771–80.
Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126(2):305–12.
Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, et al. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol. 2004;188(2):224–37.
Kohl Z, Winner B, Ubhi K, Rockenstein E, Mante M, Munch M, et al. Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. Eur J Neurosci. 2012;35(1):10–9.
Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, et al. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis. 2011;41(3):706–16.
Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bogdahn U, et al. Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging. 2008;29(6):913–25.
Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci. 2004;7(7):726–35.
Gil JM, Mohapel P, Araujo IM, Popovic N, Li JY, Brundin P, et al. Reduced hippocampal neurogenesis in R6/2 transgenic Huntington’s disease mice. Neurobiol Dis. 2005;20(3):744–51.
Kohl Z, Regensburger M, Aigner R, Kandasamy M, Winner B, Aigner L, et al. Impaired adult olfactory bulb neurogenesis in the R6/2 mouse model of Huntington’s disease. BMC Neurosci. 2010;11:114.
Simpson JM, Gil-Mohapel J, Pouladi MA, Ghilan M, Xie Y, Hayden MR, et al. Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease. Neurobiol Dis. 2011;41(2):249–60.
Phillips W, Morton AJ, Barker RA. Abnormalities of neurogenesis in the R6/2 mouse model of Huntington’s disease are attributable to the in vivo microenvironment. J Neurosci Off J Soc Neurosci. 2005;25(50):11564–76.
Liu Z, Martin LJ. The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. J Comp Neurol. 2006;497(3):468–88.
DiFebo F, Curti D, Botti F, Biella G, Bigini P, Mennini T, et al. Neural precursors (NPCs) from adult L967Q mice display early commitment to “in vitro” neuronal differentiation and hyperexcitability. Exp Neurol. 2012;236(2):307–18.
Donato SD, Mariotti C, Taroni F. Spinocerebellar ataxia type 1. Handb Clin Neurol. 2012;103:399–421.
Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun. 2015;6:6606.
Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science (New York, NY). 2004;304(5675):1338–40.
Cvetanovic M, Ingram M, Orr H, Opal P. Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience. 2015;289:289–99.
Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD. A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci. 2001;2(4):287–93.
Chintawar S, Hourez R, Ravella A, Gall D, Orduz D, Rai M, et al. Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model. J Neurosci Off J Soc Neurosci. 2009;29(42):13126–35.
Matsuura S, Shuvaev AN, Iizuka A, Nakamura K, Hirai H. Mesenchymal stem cells ameliorate cerebellar pathology in a mouse model of spinocerebellar ataxia type 1. Cerebellum (Lond, Engl). 2014;13(3):323–30.
Acknowledgments
We thank the members of the Opal lab for their intellectual input. We thank Jessica Huang for her help with the histopathology and mouse genotyping. MC was supported by startup funds for the Institute for the Translational Neuroscience and Minnesota Medical Foundation, while PO received grant support from the US National Institutes of Health (1R01 NS062051 and 1R01NS082351).
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All animal experiments were performed in compliance with National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and the Northwestern University Institutional Animal Care and Use Committee.
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The authors declare that they have no conflict of interest.
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Marija Cvetanovic and Yuan-Shih Hu contributed equally to this work.
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Cvetanovic, M., Hu, YS. & Opal, P. Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum 16, 340–347 (2017). https://doi.org/10.1007/s12311-016-0794-9
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DOI: https://doi.org/10.1007/s12311-016-0794-9