Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial Membrane Fluidity is Consistently Increased in Different Models of Huntington Disease: Restorative Effects of Olesoxime

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT). One prominent target of the mutant huntingtin protein (mhtt) is the mitochondrion, affecting its morphology, distribution, and function. Thus, mitochondria have been suggested as potential therapeutic targets for the treatment of HD. Olesoxime, a cholesterol-like compound, promotes motor neuron survival and neurite outgrowth in vitro, and its effects are presumed to occur via a direct interaction with mitochondrial membranes (MMs). We examined the properties of MMs isolated from cell and animal models of HD as well as the effects of olesoxime on MM fluidity and cholesterol levels. MMs isolated from brains of aged Hdh Q111/Q111 knock-in mice showed a significant decrease in 1,6-diphenyl-hexatriene (DPH) anisotropy, which is inversely correlated with membrane fluidity. Similar increases in MM fluidity were observed in striatal STHdh Q111/Q111 cells as well as in MMs isolated from brains of BACHD transgenic rats. Treatment of STHdh cells with olesoxime decreased the fluidity of isolated MMs. Decreased membrane fluidity was also measured in olesoxime-treated MMs isolated from brains of HD knock-in mice. In both models, treatment with olesoxime restored HD-specific changes in MMs. Accordingly, olesoxime significantly counteracted the mhtt-induced increase in MM fluidity of MMs isolated from brains of BACHD rats after 12 months of treatment in vivo, possibly by enhancing MM cholesterol levels. Thus, olesoxime may represent a novel pharmacological tool to treat mitochondrial dysfunction in HD.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AD:

Alzheimer disease

α-FGF:

Acidic fibroblast growth factor

CHOD-PAP:

Cholesteroloxidase-peroxidase-aminophenazon-phenol

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethylsulfoxide

DPH:

1,6-Diphenyl-hexatriene

EDTA:

Ethylenediamine tetra acetic acid

ETC.:

Electron transfer chain

FCS:

Fetal calf serum

HCl:

Hydrochloride

HD:

Huntington disease

HMG-CoA:

3-Hydroxy-3-methyl-glutaryl-CoA

htt :

Huntingtin gene

htt:

Huntingtin protein

HTT:

Human huntingtin gene

HEPES:

4-2-Hydroxyethyl-1-piperazineethanesulfonic acid

IBMX:

3-Isobutyl-1-methylxanthine

MβCD:

Methyl-β-cyclodextrine

mhtt:

Mutant huntingtin protein

mPT:

Mitochondrial permeability transition

PBS:

Phosphate-buffered saline

SPM:

Synaptosomal plasma membrane

TPA:

Phorbol 12-myristate 13-acetate

Tris:

Trishydroxymethylaminomethan

TUDCA:

Tauroursodeoxycholic acid

VDAC:

Voltage-dependent anion channel

References

  1. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983

    Article  Google Scholar 

  2. Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, Ross CA (1993) Correlation between the onset age of Huntington’s disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 2(10):1547–1549

    Article  PubMed  CAS  Google Scholar 

  3. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384

    Article  PubMed  CAS  Google Scholar 

  4. Nijtmans LGJ, Ugallde C, van den Heuvel LP, Smeitink JAM (2004) Function and dysfunction of the oxidative phospharylation system. In: Koehler C, Bauer MF (eds) Mitochondrial function and biogenetics. Springer Inc., Heidelberg, pp 149–167

    Chapter  Google Scholar 

  5. Wisniewska A, Draus J, Subczynski WK (2003) Is a fluid-mosaic model of biological membranes fully relevant? Studies on lipid organization in model and biological membranes. Cell Mol Biol Lett 8(1):147–159

    PubMed  CAS  Google Scholar 

  6. Helmreich EJ (2003) Environmental influences on signal transduction through membranes: a retrospective mini-review. Biophys Chem 100(1–3):519–534

    PubMed  CAS  Google Scholar 

  7. Los DA, Murata N (2004) Membrane fluidity and its roles in the perception of environmental signals. Biochim Biophys Acta 1666(1–2):142–157

    Article  PubMed  CAS  Google Scholar 

  8. Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease. Nature 438(7068):612–621

    Article  PubMed  CAS  Google Scholar 

  9. Peters I, Igbavboa U, Schutt T, Haidari S, Hartig U, Rosello X, Bottner S, Copanaki E, Deller T, Kogel D, Wood WG, Muller WE, Eckert GP (2009) The interaction of beta-amyloid protein with cellular membranes stimulates its own production. Biochim Biophys Acta 1788(5):964–972

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Fajardo VA, McMeekin L, LeBlanc PJ (2011) Influence of phospholipid species on membrane fluidity: a meta-analysis for a novel phospholipid fluidity index. J Membr Biol 244(2):97–103

    Article  PubMed  CAS  Google Scholar 

  11. Comte J, Maisterrena B, Gautheron DC (1976) Lipid composition and protein profiles of outer and inner membranes from pig heart mitochondria. Comparison with microsomes. Biochim Biophys Acta 419(2):271–284

    Article  PubMed  CAS  Google Scholar 

  12. Montecucco C, Smith GA, Dabbeni-sala F, Johannsson A, Galante YM, Bisson R (1982) Bilayer thickness and enzymatic activity in the mitochondrial cytochrome c oxidase and ATPase complex. FEBS Lett 144(1):145–148

    Article  PubMed  CAS  Google Scholar 

  13. Madden TD, Hope MJ, Cullis PR (1983) Lipid requirements for coupled cytochrome oxidase vesicles. Biochemistry 22(8):1970–1974

    Article  PubMed  CAS  Google Scholar 

  14. Ricchelli F, Gobbo S, Moreno G, Salet C (1999) Changes of the fluidity of mitochondrial membranes induced by the permeability transition. Biochemistry 38(29):9295–9300

    Article  PubMed  CAS  Google Scholar 

  15. Aleardi AM, Benard G, Augereau O, Malgat M, Talbot JC, Mazat JP, Letellier T, Dachary-Prigent J, Solaini GC, Rossignol R (2005) Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr 37(4):207–225

    Article  PubMed  CAS  Google Scholar 

  16. Colell A (2003) Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity. J Biol Chem 278(36):33928–33935

    Article  PubMed  CAS  Google Scholar 

  17. Garofalo T, Tinari A, Matarrese P, Giammarioli AM, Manganelli V, Ciarlo L, Misasi R, Sorice M, Malorni W (2007) Do mitochondria act as “cargo boats” in the journey of GD3 to the nucleus during apoptosis? FEBS Lett 581(21):3899–3903

    Article  PubMed  CAS  Google Scholar 

  18. Gouarné C, Tardif G, Tracz J, Latyszenok V, Michaud M, Clemens LE, Yu-Taeger L, Nguyen HP, Bordet T, Pruss RM (2013) Early deficits in glycolysis are specific to striatal neurons from a rat model of huntington disease. PLoS One 8(11):e81528

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jin YN, Yu YV, Gundemir S, Jo C, Cui M, Tieu K, Johnson GV (2013) Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One 8(3):e57932

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795

    Article  PubMed  CAS  Google Scholar 

  21. Browne SE (2008) Mitochondria and Huntington’s disease pathogenesis: insight from genetic and chemical models. Ann N Y Acad Sci 1147:358–382

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Oliveira JM (2010) Mitochondrial bioenergetics and dynamics in Huntington’s disease: tripartite synapses and selective striatal degeneration. J Bioenerg Biomembr 42(3):227–234

    Article  PubMed  CAS  Google Scholar 

  24. Rosenstock TR, Duarte AI, Rego AC (2010) Mitochondrial-associated metabolic changes and neurodegeneration in Huntington’s disease—from clinical features to the bench. Curr Drug Targets 11(10):1218–1236

    Article  PubMed  CAS  Google Scholar 

  25. Choo YS, Johnson GVW, MacDonald M, Detloff PJ, Lesort M (2004) Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 13(14):1407–1420

    Article  PubMed  CAS  Google Scholar 

  26. Gellerich FN, Gizatullina Z, Nguyen HP, Trumbeckaite S, Vielhaber S, Seppet E, Zierz S, Landwehrmeyer B, Riess O, von Horsten S, Striggow F (2008) Impaired regulation of brain mitochondria by extramitochondrial Ca2+ in transgenic Huntington disease rats. J Biol Chem 283(45):30715–30724

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 28(11):2783–2792

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Wang H, Lim PJ, Karbowski M, Monteiro MJ (2009) Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18(4):737–752

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Costa V, Giacomello M, Hudec R, Lopreiato R, Ermak G, Lim D, Malorni W, Davies KJ, Carafoli E, Scorrano L (2010) Mitochondrial fission and cristae disruption increase the response of cell models of Huntington’s disease to apoptotic stimuli. EMBO Mol Med 2(12):490–503

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet 19(20):3919–3935

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet 20(7):1438–1455

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17(3):377–382

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, Tran DD, Vrieze BT, Legendre-Guillemin V, McPherson PS, Mandavilli BS, Van Houten B, Zeitlin S, McNiven M, Aebersold R, Hayden M, Parisi JE, Seeberg E, Dragatsis I, Doyle K, Bender A, Chacko C, McMurray CT (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24(18):8195–8209

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Panov AV, Gutekunst C-A, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5(8):731–736

    PubMed  CAS  Google Scholar 

  35. Milakovic T, Johnson GV (2005) Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem 280(35):30773–30782

    Article  PubMed  CAS  Google Scholar 

  36. Goety CG, Tanner CM, Cohen JA, Thelen JA, Carroll VS, Klawans HL, Fariello RG (1990) l-Acetyl-carnitine in Huntington’s disease: double-blind placebo controlled crossover study of drug effects on movement disorder and dementia. Mov Disord 5(3):263–265

    Article  PubMed  CAS  Google Scholar 

  37. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22(5):1592–1599

    PubMed  CAS  Google Scholar 

  38. Vamos E, Voros K, Vecsei L, Klivenyi P (2010) Neuroprotective effects of l-carnitine in a transgenic animal model of Huntington’s disease. Biomed Pharmacother 64(4):282–286

    Article  PubMed  CAS  Google Scholar 

  39. Hickey MA, Zhu C, Medvedeva V, Franich NR, Levine MS, Chesselet MF (2012) Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington’s disease. Mol Cell Neurosci 49(2):149–157

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, Wille E, Chandra A, Beal MF (2012) Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet 21(5):1124–1137

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Sandhir R, Sood A, Mehrotra A, Kamboj SS (2012) N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington’s disease. Neurodegener Dis 9(3):145–157

    Article  PubMed  CAS  Google Scholar 

  42. Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P, Akentieva NP, Evers AS, Covey DF, Ostuni MA, Lacapere JJ, Massaad C, Schumacher M, Steidl EM, Maux D, Delaage M, Henderson CE, Pruss RM (2007) Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 322(2):709–720

    Article  PubMed  CAS  Google Scholar 

  43. Gincel D, Zaid H, Shoshan-Barmatz V (2001) Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J 358(Pt 1):147–155

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 31(3):227–285

    Article  PubMed  CAS  Google Scholar 

  45. Hu J, Zhang Z, Shen WJ, Azhar S (2010) Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond) 7:47

    Article  Google Scholar 

  46. Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, Aebischer J, Latyszenok V, Gouarné C, Raoul C, Pruss RM, Bordet T, Pettmann B (2012) Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology 62(7):2346–2352

    Article  PubMed  CAS  Google Scholar 

  47. Xiao WH, Zheng FY, Bennett GJ, Bordet T, Pruss RM (2009) Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel. Pain 147(1–3):202–209

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Xiao WH, Zheng H, Bennett GJ (2012) Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience 203:194–206

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Bordet T, Berna P, Abitbol JL, Pruss R (2010) Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals (Basel) 3:345–368

    Article  CAS  Google Scholar 

  50. Eckmann J, Eckert SH, Leuner K, Muller WE, Eckert GP (2013) Mitochondria: mitochondrial membranes in brain ageing and neurodegeneration. Int J Biochem Cell Biol 45:76–80

    Article  PubMed  CAS  Google Scholar 

  51. Yu-Taeger L, Petrasch-Parwez E, Osmand AP, Redensek A, Metzger S, Clemens LE, Park L, Howland D, Calaminus C, Gu X, Pichler B, Yang XW, Riess O, Nguyen HP (2012) A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J Neurosci 32(44):15426–15438

    Article  PubMed  CAS  Google Scholar 

  52. Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang XW (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28(24):6182–6195

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Eckert GP, Wood WG, Muller WE (2001) Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J Neural Transm 108(8–9):1051–1064

    Article  PubMed  CAS  Google Scholar 

  54. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  55. Kirsch C, Eckert GP, Muller WE (2003) Statins affect cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 65(5):843–856

    Article  PubMed  CAS  Google Scholar 

  56. Kirsch C, Eckert GP, Mueller WE (2002) Cholesterol attenuates the membrane perturbing properties of beta-amyloid peptides. Amyloid 9(3):149–159

    Article  PubMed  CAS  Google Scholar 

  57. Choe M, Jackson C, Yu BP (1995) Lipid peroxidation contributes to age-related membrane rigidity. Free Radic Biol Med 18(6):977–984

    Article  PubMed  CAS  Google Scholar 

  58. Lentz BR (1988) Membrane fluidity from anisotropy measurements. In: Loew LM (ed) Spectroscopic membrane probes, vol 1. CRC, Boca Raton, pp 13–42

  59. Tellez-Nagel I, Johnson AB, Terry RD (1974) Studies on brain biopsies of patients with Huntington’s chorea. J Neuropathol Exp Neurol 33(2):308–332

    Article  PubMed  CAS  Google Scholar 

  60. Goebel HH, Heipertz R, Scholz W, Iqbal K, Tellez-Nagel I (1978) Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies. Neurology 28(1):23–31

    Article  PubMed  CAS  Google Scholar 

  61. Gines S, Seong IS, Fossale E, Ivanova E, Trettel F, Gusella JF, Wheeler VC, Persichetti F, MacDonald ME (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum Mol Genet 12(5):497–508

    Article  PubMed  CAS  Google Scholar 

  62. Petrasch-Parwez E, Nguyen HP, Lobbecke-Schumacher M, Habbes HW, Wieczorek S, Riess O, Andres KH, Dermietzel R, Von Horsten S (2007) Cellular and subcellular localization of Huntingtin [corrected] aggregates in the brain of a rat transgenic for Huntington disease. J Comp Neurol 501(5):716–730

    Article  PubMed  Google Scholar 

  63. Turner C, Schapira AH (2010) Mitochondrial matters of the brain: the role in Huntington’s disease. J Bioenerg Biomembr 42(3):193–198

    Article  PubMed  CAS  Google Scholar 

  64. Ciarlo L, Manganelli V, Matarrese P, Garofalo T, Tinari A, Gambardella L, Marconi M, Grasso M, Misasi R, Sorice M, Malorni W (2012) Raft-like microdomains play a key role in mitochondrial impairment in lymphoid cells from patients with Huntington’s disease. J Lipid Res 53(10):2057–2068

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS, Sensi SL, Thompson LM (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16(1):61–77

    Article  PubMed  CAS  Google Scholar 

  66. LaFontaine MA, Geddes JW, Butterfield DA (2002) 3-nitropropionic acid-induced changes in bilayer fluidity in synaptosomal membranes: implications for Huntington’s disease 1. Neurochem Res 27(6):507–511

    Article  PubMed  CAS  Google Scholar 

  67. Brouillet E, Conde F, Beal MF, Hantraye P (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog Neurobiol 59(5):427–468

    Article  PubMed  CAS  Google Scholar 

  68. Schroeder F, Goetz IE, Roberts E (1984) Membrane anomalies in Huntington’s disease fibroblasts. J Neurochem 43(2):526–539

    Article  PubMed  CAS  Google Scholar 

  69. Eckert GP, Igbavboa U, Muller WE, Wood WG (2003) Lipid rafts of purified mouse brain synaptosomes prepared with or without detergent reveal different lipid and protein domains. Brain Res 962(1–2):144–150

    Article  PubMed  CAS  Google Scholar 

  70. Eckert GP, Muller WE (2009) Presenilin 1 modifies lipid raft composition of neuronal membranes. Biochem Biophys Res Commun 382(4):673–677

    Article  PubMed  CAS  Google Scholar 

  71. Wood WG, Igbavboa U, Muller WE, Eckert GP (2011) Cholesterol asymmetry in synaptic plasma membranes. J Neurosci 116(5):684–689

    CAS  Google Scholar 

  72. Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I (2010) Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol 4(1):17–23

    Article  PubMed  PubMed Central  Google Scholar 

  73. Karasinska JM, Hayden MR (2011) Cholesterol metabolism in Huntington disease. Nat Rev Neurol 7(10):561–572

    Article  PubMed  CAS  Google Scholar 

  74. Valenza M, Cattaneo E (2011) Emerging roles for cholesterol in Huntington’s disease. Trends Neurosci 34(9):474–486

    Article  PubMed  CAS  Google Scholar 

  75. Leoni V, Caccia C (2013) 24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases. Biochimie 95(3):595–612

    Article  PubMed  CAS  Google Scholar 

  76. Valenza M, Leoni V, Karasinska JM, Petricca L, Fan J, Carroll J, Pouladi MA, Fossale E, Nguyen HP, Riess O, MacDonald M, Wellington C, DiDonato S, Hayden M, Cattaneo E (2010) Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci 30(32):10844–10850

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  77. Marullo M, Valenza M, Leoni V, Caccia C, Scarlatti C, De Mario A, Zuccato C, Di Donato S, Carafoli E, Cattaneo E (2012) Pitfalls in the detection of cholesterol in Huntington’s disease models. PLoS Curr 4:e505886e9a1968

    Google Scholar 

  78. Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, Beal MF (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci U S A 92(15):7105–7109

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Damiano M, Galvan L, Deglon N, Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1802(1):52–61

    Article  PubMed  CAS  Google Scholar 

  80. Burchell VS, Gandhi S, Deas E, Wood NW, Abramov AY, Plun-Favreau H (2010) Targeting mitochondrial dysfunction in neurodegenerative disease: part II. Expert Opin Ther Targets 14(5):497–511

    Article  PubMed  CAS  Google Scholar 

  81. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, Perry G, Smith MA (2010) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802(1):212–220

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Shoshan-Barmatz V, Ben-Hail D (2012) VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion 12(1):24–34

    Article  PubMed  CAS  Google Scholar 

  83. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9(12):971–988

    Article  PubMed  CAS  Google Scholar 

  84. Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G (2007) Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands. Neuropharmacology 53(2):318–329

    Article  PubMed  CAS  Google Scholar 

  85. Miccoli L, Oudard S, Beurdeley-Thomas A, Dutrillaux B, Poupon MF (1999) Effect of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), a specific ligand of the peripheral benzodiazepine receptor, on the lipid fluidity of mitochondria in human glioma cells. Biochem Pharmacol 58(4):715–721

    Article  PubMed  CAS  Google Scholar 

  86. Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM (2003) Chenodeoxycholate induction of mitochondrial permeability transition pore is associated with increased membrane fluidity and cytochrome c release: protective role of carvedilol. Mitochondrion 2(4):305–311

    Article  PubMed  CAS  Google Scholar 

  87. Mattson MP, Liu D (2003) Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochem Biophys Res Commun 304(3):539–549

    Article  PubMed  CAS  Google Scholar 

  88. Jana NR, Zemskov EA, Wang G, Nukina N (2001) Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 10(10):1049–1059

    Article  PubMed  CAS  Google Scholar 

  89. Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283(9):5780–5789

    Article  PubMed  CAS  Google Scholar 

  90. Wang X, Zhu S, Pei Z, Drozda M, Stavrovskaya IG, Del Signore SJ, Cormier K, Shimony EM, Wang H, Ferrante RJ, Kristal BS, Friedlander RM (2008) Inhibitors of cytochrome c release with therapeutic potential for Huntington’s disease. J Neurosci 28(38):9473–9485

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  91. Magalon K, Zimmer C, Cayre M, Khaldi J, Bourbon C, Robles I, Tardif G, Viola A, Pruss RM, Bordet T, Durbec P (2012) Olesoxime accelerates myelination and promotes repair in models of demyelination. Ann Neurol 71(2):213–226

    Article  PubMed  CAS  Google Scholar 

  92. Rivard AL, Steer CJ, Kren BT, Rodrigues CM, Castro RE, Bianco RW, Low WC (2007) Administration of tauroursodeoxycholic acid (TUDCA) reduces apoptosis following myocardial infarction in rat. Am J Chin Med 35(2):279–295

    Article  PubMed  CAS  Google Scholar 

  93. Rodrigues CM, Stieers CL, Keene CD, Ma X, Kren BT, Low WC, Steer CJ (2000) Tauroursodeoxycholic acid partially prevents apoptosis induced by 3-nitropropionic acid: evidence for a mitochondrial pathway independent of the permeability transition. J Neurochem 75(6):2368–2379

    Article  PubMed  CAS  Google Scholar 

  94. Keene CD, Rodrigues CM, Eich T, Linehan-Stieers C, Abt A, Kren BT, Steer CJ, Low WC (2001) A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington’s disease. Exp Neurol 171(2):351–360

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The data presented herein were assessed in the framework of the seventh framework program for RTD of the European Union—Project MitoTarget—(Grant Agreement HEALTH-F2-2008-223388). We are grateful to all MitoTarget members for their helpful discussions. We further thank Martina Piekorz and Therese Stanek for their excellent support in animal care.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Biocenter, Goethe-University Campus Riedberg, Biocentre Geb. N260, R.1.09, Max-von-Laue Str. 9, 60438, Frankfurt, Germany

    Janett Eckmann, Schamim H. Eckert, Stephanie Hagl, Walter E. Muller, Kristina Leuner & Gunter P. Eckert

  2. Institute of Medical Genetics and Applied Genomics, and Centre for Rare Diseases, University of Tuebingen, Calwerstr. 7, 72076, Tuebingen, Germany

    Laura E. Clemens, Libo Yu-Taeger & Huu P. Nguyen

  3. Discovery Research, Trophos SA, Parc Scientifique de Luminy - Case 931, 13288, Marseille, France

    Thierry Bordet & Rebecca M. Pruss

  4. Molecular and Clinical Pharmacy, University of Erlangen-Nuremberg, Erlangen, Germany

    Kristina Leuner

Authors
  1. Janett Eckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura E. Clemens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Schamim H. Eckert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie Hagl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Libo Yu-Taeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thierry Bordet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rebecca M. Pruss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Walter E. Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kristina Leuner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Huu P. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gunter P. Eckert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gunter P. Eckert.

Additional information

Janett Eckmann, Laura E. Clemens, Huu P. Nguyen, and Gunter P. Eckert contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eckmann, J., Clemens, L.E., Eckert, S.H. et al. Mitochondrial Membrane Fluidity is Consistently Increased in Different Models of Huntington Disease: Restorative Effects of Olesoxime. Mol Neurobiol 50, 107–118 (2014). https://doi.org/10.1007/s12035-014-8663-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8663-3

Keywords

Search

Navigation