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Mitochondrial matters of the brain: the role in Huntington’s disease

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Abstract

Even before the discovery of the mutant htt gene as the cause of Huntington’s Disease (HD), abnormal energy metabolism and mitochondrial dysfunction had been suggested as a possible pathogenic mechanism in HD. These initial investigations described defects in energy metabolism using Positron Emission Tomography (PET) and Nuclear Magnetic Resonance (NMR) Spectroscopy in symptomatic and pre-symptomatic HD patients. Concurrently, 3-nitroproprionic acid, a mitochondrial complex II inhibitor, was found to replicate many of the pathological and clinical features of HD when administered to animals. Subsequently, reductions in mitochondrial respiratory chain enzyme activities in HD brain and muscle, HD mice models and cellular HD models were discovered and confirmed impaired mitochondrial function as an important component of pathogenesis. A unifying hypothesis linking chronic ATP depletion, oxidative stress and mitochondrial dysfunction culminated in the “slow excitotoxic theory” of HD pathogenesis. More recently, the localization of mutant htt within mitochondria and the association between transcriptional dysregulation caused by impaired PGC-1α activity with abnormal mitochondrial biogenesis and function has provided further links with additional potential pathogenic mechanisms.

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References

  • Alam ZI, Halliwell B, Jenner P (2000) J Neurochem 75:840–846

    Article  CAS  Google Scholar 

  • Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD et al (1990) N Engl J Med 3322(18):1293–1298

    Google Scholar 

  • Albin RL, Greenamyre JT (1992) Neurology 42(4):733–738

    CAS  Google Scholar 

  • Alexi T, Hughes PE, Faull RL, Williams CE (1998) NeuroReport 9:R57–R64

    Article  CAS  Google Scholar 

  • Arenas J, Campos Y, Ribacoba R, Martin MA, Rubio JC, Ablanedo P, Cabello A (1998) Complex I defect in muscle from patients with Huntington’s disease. Ann Neurol 43:397–400

    Article  CAS  Google Scholar 

  • Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM et al (1993a) J Neurosci 13:4181–4192

    CAS  Google Scholar 

  • Beal MF, Brouillet E, Jenkins BG, Henshaw R, Rosen BR, Hyman BT (1993b) J Neurochem 61:1147–1150

    Article  CAS  Google Scholar 

  • Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB (1994) Ann Neurol 36:882–888

    Article  CAS  Google Scholar 

  • Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N et al (2006) Mol Biol Cell 17(4):1652–1663

    Article  CAS  Google Scholar 

  • Bogdanov M, Ferrante RJ, Kuemmerle S, Klivenyi P, Beal MF (1998) J Neurochem 71:2642–2644

    Article  CAS  Google Scholar 

  • Brennan WA Jr, Bird ED, Aprille JR (1985) Regional mitochondrial respiratory activity in Huntington’s disease brain. J Neurochem 44:1948–1950

    Article  CAS  Google Scholar 

  • Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM et al (1997) Ann Neurol 41:646–653

    Article  CAS  Google Scholar 

  • Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, Dragunow M (1998) Neuroscience 87:49–53

    Article  CAS  Google Scholar 

  • Chang DTW, Rintoul GL, Pandipati S, Reynolds I (2006) Neurobiol Dis 22:388–400

    Article  CAS  Google Scholar 

  • Choo YS, Johnson GVW, MacDonald M, Detloff PJ, Lesort M (2004) Hum Mol Genet 13:1407–1420

    Article  CAS  Google Scholar 

  • Chyi T, Chang C (1999) Neurosci 92:1035–1041

    Article  CAS  Google Scholar 

  • Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH (2008) Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur J Neurol 15:1371–1379

    Article  CAS  Google Scholar 

  • Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Cell 127(1):59–69

    Article  CAS  Google Scholar 

  • Cull-Candy S, Brickley S, Farrant M (2001) Curr Opin Neurobiol 11:327–335

    Article  CAS  Google Scholar 

  • Dautry C, Conde F, Brouillet E, Mittoux V, Beal MF, Bloch G et al (1999) Neurobiol Dis 6:259–268

    Article  CAS  Google Scholar 

  • Dejean LM, Martinez-Caballero S, Kinnally KW (2006) Cell Death and Differentiation 13:1387–1395

    Article  CAS  Google Scholar 

  • Favit A, Nicoletti F, Scapagnini U, Canonico PL (1992) J Cereb Blood Flow Metab 12:638–645

    CAS  Google Scholar 

  • Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK et al (2000) J Neurosci 20:4389–4397

    CAS  Google Scholar 

  • Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) J Neurosci 22:1592–1599

    CAS  Google Scholar 

  • Fukui H, Moraes CT (2007) Hum Mol Gen 16(7):783–797

    Article  CAS  Google Scholar 

  • Grafton ST, Mazziotta JC, Pahl JJ, St George-Hyslop P, Haines JL, Gusella J et al (1990) Ann Neurol 5:614–621

    Article  Google Scholar 

  • Greco A, Minghetti L, Levi G (2000) Neurochem Res 25:1357–1364

    Article  CAS  Google Scholar 

  • Gu M, Gash MT, Mann VM, Javoy-Agod F, Cooper JM, Schapira AH (1996) Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 39(3):385–389

    Google Scholar 

  • Harms L, Meierkord H, Timm G, Pfeiffer L, Ludolph AC (1997) J Neurol Neurosurg Psychiatry 62:27–30

    Article  CAS  Google Scholar 

  • Hart PE, Lodi R, Rajagopalan B, Bradley JL, Crilley JG, Turner C et al (2005) Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol 62:621–626

    Article  Google Scholar 

  • Group HS (2001) Neurology 57:397–404

    Google Scholar 

  • Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Neurology 43:2689–2695

    CAS  Google Scholar 

  • Jenkins BG, Rosas HD, Chen YCI, Makabe T, Myers R, MacDonald M et al (1998) Neurology 50:1357–1365

    CAS  Google Scholar 

  • Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF (1997) Ann Neurol 41:160–165

    Article  CAS  Google Scholar 

  • Kuwert T, Lange HW, Langen K-J, Herzog H, Albrecht A, Feinendegen LE (1990) Brain 113:1405–1423

    Article  Google Scholar 

  • Kuwert T, Lange HW, Boecker H, Titz H, Herzog H, Aulich A et al (1993) J Neurol 241:31–36

    Article  CAS  Google Scholar 

  • La Fontaine MA, Geddes JW, Banks A, Butterfield DA (2000) Brain Res 858:356–362

    Article  Google Scholar 

  • Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S et al (2005) PLoS Biol 3:e101

    Article  CAS  Google Scholar 

  • Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O et al (2002) Nature 418:797–801

    Article  CAS  Google Scholar 

  • Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ et al (2000) Ann Neurol 48:72–76

    Article  CAS  Google Scholar 

  • Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) Can J Neurol Sci 18:492–498

    CAS  Google Scholar 

  • Mann VM, Cooper JM, Javoy-Agid F, Agid Y, Jenner P, Schapira AH (1990) Mitochondrial function and parental sex effect in Huntington’s disease. Lancet 336:749

    Article  CAS  Google Scholar 

  • Martin WRW, Clark C, Ammann W, Stoessl AJ, Shtybel W, Hayden MR (1992) Neurology 42:223–229

    CAS  Google Scholar 

  • Martin WRW, Hanstock C, Hodder J, Allen JS (1996) Ann Neurol 40:538

    Google Scholar 

  • Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R et al (1998) J Neurosci 18:156–163

    CAS  Google Scholar 

  • McBride HM, Neuspiel M, Wasiak S (2006) Curr Biol 16(14):R551–R560

    Article  CAS  Google Scholar 

  • Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y, Milner DJ (2000) J Cell Biol 150:1283–1298

    Article  CAS  Google Scholar 

  • Morgan-Hughes JA, Schapira AH, Cooper JM, Clark JB (1988) Molecular defects of NADH-ubiquinone oxidoreductase (complex I) in mitochondrial diseases. J Bioenerg Biomembr 20:365–382

    Article  CAS  Google Scholar 

  • Myers RH, Sax DS, Koroshetz WJ, Mastromauro C, Cupples LA, Kiely DK et al (1991) Arch Neurol 48:800–804

    CAS  Google Scholar 

  • Owen AD, Schapira AH, Jenner P, Marsden CD (1996) Oxidative stress and Parkinson’s disease. Ann NY Acad Sci 786:217–223

    Article  CAS  Google Scholar 

  • Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ et al (2002) Nat Neurosci 5(8):731–736

    CAS  Google Scholar 

  • Parker WD Jr, Boyson SJ, Luder AS, Parks JK (1990) Evidence for a defect in NADH: ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 40(8):1231–1234

    Google Scholar 

  • Patel M, Day BJ, Crapo JD, Fridowich I, McNamara JO (1996) Neuron 16:345–355

    Article  CAS  Google Scholar 

  • Perez-Severiano F, Rios C, Segovia J (2000) Brain Res 862:234–237

    Article  CAS  Google Scholar 

  • Petrasch-Parwez E, Nguyen HP, Lobbecke-Schumacher M, Habbes HW, Wieczorek S, Riess O et al (2007) J Comp Neurol 501(5):716–730

    Article  Google Scholar 

  • Pratley RE, Salbe AD, Ravussin E, Caviness JN (2000) Ann Neurol 47:64–70

    Article  CAS  Google Scholar 

  • Raymond L (2003) Clin Neurosci Res 3(3):121–128

    Article  CAS  Google Scholar 

  • Rizzuto R (2001) Curr Op Neurobiol 11:306–311

    Article  CAS  Google Scholar 

  • Sanchez-Pernaute R, Garcia-Segura JM, del Barrio Alba A, Viano J, de Yebenes JG (1999) Neurology 53:806

    CAS  Google Scholar 

  • Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler JF Jr, Greenamyre JT, Snyder SH, Ross CA (1999) Increased apoptosis of Huntington disease lymphoblast associated with repeat length-dependent mitochondrial depolarization. Nat Med 5:1194–1198

    Article  CAS  Google Scholar 

  • Schapira AH (2006) Mitochondrial disease. Lancet 368:70–82

    Article  CAS  Google Scholar 

  • Schapira AH (1995) Oxidative stress in Parkinson’s disease. Neuropathol Appl Neurobiol 21:3–9

    Article  CAS  Google Scholar 

  • Schapira AH, Cooper JM, Morgan-Hughes JA et al (1988) Molecular basis of mitochondrial myopathies: polypeptide analysis in complex-I deficiency. Lancet 1:500–503

    Article  CAS  Google Scholar 

  • Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M et al (2005) Hum Mol Genet 14:2871–2880

    Article  CAS  Google Scholar 

  • Solans A, Zambrano A, Rodríguez M, Barrientos A (2006) Hum Mol Genet 15(20):3063–3081

    Article  CAS  Google Scholar 

  • Stahl WL, Swanson PD (1974) Biochemical abnormalities in Huntington’s chorea brains. Neurology 24:813–819

    CAS  Google Scholar 

  • Tabrizi SJ, Cleeter MWJ, Xuereb J, Taanman JW, Cooper JM, Schapira AHV (1999) Ann Neurol 45:25–32

    Article  CAS  Google Scholar 

  • Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A, Bates G et al (2000) Ann Neurol 47:80–86

    Article  CAS  Google Scholar 

  • Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH et al (2005) Neurology 64(9):1655–1656

    Article  CAS  Google Scholar 

  • Thomas PK, Cooper JM, King RH, Workman JM, Schapira AH, Goss-Sampson MA, Muller DP (1993) Myopathy in vitamin E deficient rats: muscle fibre necrosis associated with disturbances of mitochondrial function. J Anat 183:451–461

    Google Scholar 

  • Turner C, Cooper JM, Schapira AH (2007) Clinical corralates of mitochondrial function in Huntington’s disease muscle. Mov Disord 22(12):1715–1721

    Article  Google Scholar 

  • Wyttenbach A, Swartz J, Kita H, Thykjaer T, Carmichael J, Bradley J et al (2001) Hum Mol Genet 10(17):1829–1845

    Article  CAS  Google Scholar 

  • Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P et al (2002) Neuron 33:849–860

    Article  CAS  Google Scholar 

  • Zeron MM, Fernandes HB, Krebs C, Shehadeh J, Wellington CL, Leavitt BR et al (2004) Mol Cell Neurosci 25:469–479

    Article  CAS  Google Scholar 

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Correspondence to A. H. V. Schapira.

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This review will briefly summarise the evidence for mitochondrial dysfunction in HD and how this may affect strategies for future treatments.

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Turner, C., Schapira, A.H.V. Mitochondrial matters of the brain: the role in Huntington’s disease. J Bioenerg Biomembr 42, 193–198 (2010). https://doi.org/10.1007/s10863-010-9290-y

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