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Drugs & Aging

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01.02.2007 | Leading Article

Role of Mitochondrial Dysfunction in Parkinson’s Disease

Implications for Treatment

verfasst von: Chenere P. Ramsey, Dr Benoit I. Giasson

Erschienen in: Drugs & Aging | Ausgabe 2/2007

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Abstract

The role of mitochondrial dysfunction as a possible cause of parkinsonism became apparent in the mid-1980s with the discovery of a group of individuals with chronic parkinsonism who had been exposed to the chemical l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and the subsequent elucidation of the mode of action of this toxin as a mitochondrial complex I inhibitor. Thereafter, a defect in mitochondrial complex I was supported by biochemical studies in patients with sporadic Parkinson’s disease. Recently, striking genetic findings and biological studies have further substantiated that mitochondrial dysfunction is likely an important disease mechanism in a significant percentage, if not the majority, of patients with Parkinson’s disease. These findings have defined novel biochemical pathways that can directly or indirectly affect mitochondrial function and/or integrity. Although various primary insults (genetic or environmental factors) are involved in the aetiology of Parkinson’s disease, emerging evidence supports the notion that attempting to prevent or compensate for mitochondrial dysfunction could have therapeutic benefits for a majority of patients with Parkinson’s disease.

Simuni T, Hurtig HI. Parkinson’s disease: the clinical picture. In: Clark CM, Trojanoswki JQ, editors. Neurodegenerative dementias. New York: McGraw-Hill, 2000: 193–203

Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 1996 Mar; 55(3): 259–72PubMedCrossRef

Damier P, Hirsch EC, Agid Y, et al. The substantia nigra of the human brain: II -patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 1999 Aug; 122 (Pt 8): 1437–48PubMedCrossRef

Pakkenberg B, Moller A, Gundersen HJ, et al. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry 1991 Jan; 54(1): 30–3PubMedCrossRef

Mayeau R, Stern Y, Cote L, et al. Altered serotonin metabolism in depressed patients with Parkinson’s disease. Neurology 1984 May; 34(5): 642–6CrossRef

Forman MS, Lee VM, Trojanowski JQ. Nosology of Parkinson’s disease: looking for the way out of a quackmire. Neuron 2005 Aug 18; 47(4): 479–82PubMedCrossRef

Moore DJ, West AB, Dawson VL, et al. Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 2005; 28: 57–87PubMedCrossRef

Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003 Mar; 24(2): 197–211PubMedCrossRef

Norris EH, Giasson BI, Lee VM. Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 2004; 60: 17–54PubMedCrossRef

10.

George JM. The synucleins. Genome Biol 2002; 3(1): REVIEWS3002

11.

Duda JE, Lee VMY, Trojanowski JQ. Neuropathology of synuclein aggregates. J Neurosci Res 2000 Jul 15; 61(2): 121–7PubMedCrossRef

12.

George JM, Jin H, Woods WS, et al. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 1995 Aug; 15(2): 361–72PubMedCrossRef

13.

Iwai A, Masliah E, Yoshimoto M, et al. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995 Feb; 14(2): 467–75PubMedCrossRef

14.

Withers GS, George JM, Banker GA, et al. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res 1997 Mar 17; 99(1): 87–94PubMedCrossRef

15.

Abeliovich A, Schmitz Y, Farinas I, et al. Mice lacking alphasynuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000 Jan; 25(1): 239–52PubMedCrossRef

16.

Chandra S, Fornai F, Kwon HB, et al. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A 2004 Oct 12; 101(41): 14966–71PubMedCrossRef

17.

Chandra S, Gallardo G, Fernández-Chacón R, et al. Alphasynuclein cooperates with CSP alpha in preventing neurodegeneration. Cell 2005 Nov 4; 123(3): 383–96PubMedCrossRef

18.

Fernandez-Chacon R, Wolfel M, Nishimune H, et al. The synaptic vesicle protein CSP alpha prevents presynaptic degeneration. Neuron 2004 Apr 22; 42(2): 237–51PubMedCrossRef

19.

Ungar D, Hughson FM. SNARE protein structure and function. Annu Rev Cell Dev Biol 2003; 19: 493–517PubMedCrossRef

20.

Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997 Jun 27; 276(5321): 2045–7PubMedCrossRef

21.

Markopoulou K, Wszolek ZK, Pfeiffer RF, et al. Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism. Ann Neurol 1999 Sep; 46(3): 374–81PubMedCrossRef

22.

Athanassiadou A, Voutsinas G, Psiouri L, et al. Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding alpha-synuclein. Am J Hum Genet 1999 Aug; 65(2): 555–8PubMedCrossRef

23.

Papadimitriou A, Veletza V, Hadjigeorgiou GM, et al. Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 1999 Feb; 52(3): 651–4PubMedCrossRef

24.

Spira PJ, Sharpe DM, Halliday G, et al. Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 2001 Mar; 49(3): 313–9PubMedCrossRef

25.

Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 1998 Feb; 18(2): 106–8PubMedCrossRef

26.

Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004 Feb; 55(2): 164–73PubMedCrossRef

27.

Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003 Oct 31; 302(5646): 841PubMedCrossRef

28.

Farrer M, Kachergus J, Forno L, et al. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004 Feb; 55(2): 174–9PubMedCrossRef

29.

Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alphasynuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 2004 Sep 25; 364(9440): 1167–9PubMedCrossRef

30.

Spillantini MG, Schmidt ML, Lee VMY, et al. Alpha-synuclein in Lewy bodies. Nature 1997 Aug 28; 388(6645): 839–40PubMedCrossRef

31.

Spillantini MG, Crowther RA, Jakes R, et al. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 1998 May 26; 95(11): 6469–73PubMedCrossRef

32.

Spillantini MG, Crowther RA, Jakes R, et al. Filamentous alphasynuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 1998 Jul 31; 251(3): 205–8PubMedCrossRef

33.

Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998 Sep; 44(3): 415–22PubMedCrossRef

34.

Takeda A, Mallory M, Sundsmo M, et al. Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 1998 Feb; 152(2): 367–72PubMed

35.

Irizarry MC, Growdon W, Gomez-Isla T, et al. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain alphasynuclein immunoreactivity. J Neuropathol Exp Neurol 1998 Apr; 57(4): 334–7PubMedCrossRef

36.

Giasson BI, Uryu K, Trojanowski JQ, et al. Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 1999 Mar 19; 274(12): 7619–22PubMedCrossRef

37.

Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to earlyonset Parkinson disease. Nat Med 1998 Nov; 4(11): 1318–20PubMedCrossRef

38.

Hashimoto M, Hsu LJ, Sisk A, et al. Human recombinant NACP/alpha-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease. Brain Res 1998 Jul 20; 799(2): 301–6PubMedCrossRef

39.

Narhi L, Wood SJ, Steavenson S, et al. Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 1999 Apr 2; 274(14): 9843–6PubMedCrossRef

40.

Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2001; 2: 492–501PubMedCrossRef

41.

Greenbaum EA, Graves CL, Mishizen-Eberz AJ, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 2005 Mar 4; 280(9): 7800–7PubMedCrossRef

42.

Giasson BI, Duda JE, Quinn SM, et al. Neuronal a-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 2002 May 16; 34(4): 521–33PubMedCrossRef

43.

Lee MK, Stirling W, Xu Y, et al. Human alpha-synucleinharboring familial Parkinson’s disease-linked Ala-53 —> Thr mutation causes neurodegenerative disease with alphasynuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 2002 Jun 25; 99(13): 8968–73PubMedCrossRef

44.

Goldberg MS, Lansbury PT. Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat Cell Biol 2000 Jul; 2(7): E115–9PubMedCrossRef

45.

Langsten JW, Ballard P, Tetrad JW, et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983 Feb 25; 219(4587): 979–80CrossRef

46.

Javitch JA, D’Amato RJ, Strittmatter SM, et al. Parkinsonisminducing neurotoxin, N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A 1985 Apr; 82(7): 2173–7PubMedCrossRef

47.

Przedborski S, Jackson-Lewis V. Mechanisms of MPTP toxicity. Mov Disord 1998; 13Suppl. 1: 35–8PubMed

48.

Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by l-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, l-methyl-4-phenyl1,2,5,6-tetrahydropyridine. Life Sci 1985; 36(26): 2503–8PubMedCrossRef

49.

Langsten JW, Fomo LS, Tetrad J, et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine exposure. Ann Neurol 1999 Oct; 46(4): 598–605CrossRef

50.

Ballard PA, Tetrad JW, Langsten JW. Permanent human parkinsonism due to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985 Jul; 35(7): 949–56PubMedCrossRef

51.

Shimoji M, Zhang L, Mandir AS, et al. Absence of inclusion body formation in the MPTP mouse model of Parkinson’s disease. Brain Res Mol Brain Res 2005 Mar 24; 134(1): 103–8PubMedCrossRef

52.

Fornai F, Schluter OM, Lenzi P, et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A 2005 Mar 1; 102(9): 3413–8PubMedCrossRef

53.

Drolet RE, Behrouz B, Lookingland KJ, et al. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 2004 Sep; 25(5): 761–9PubMedCrossRef

54.

Schluter OM, Fornai F, Alessandri MG, et al. Role of alphasynuclein in l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 2003; 118(4): 985–1002PubMedCrossRef

55.

Dauer W, Kholodilov N, Vila M, et al. Resistance of alphasynuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A 2002 Oct 29; 99(22): 14524–9PubMedCrossRef

56.

Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000 Dec; 3(12): 1301–6PubMedCrossRef

57.

Janetzky B, Hauck S, Youdim MB, et al. Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson’s disease. Neurosci Lett 1994 Mar 14; 169(1–2): 126–8PubMedCrossRef

58.

Muftuoglu M, Elibol B, Dalmizrak O, et al. Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov Disord 2004 May; 19(5): 544–8PubMedCrossRef

59.

Schapira AH, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990 Dec; 55(6): 2142–5PubMedCrossRef

60.

Gu M, Cooper JM, Taanman JW, et al. Mitochondrial DNA transmission of the mitochondrial defect in Parkinson’s disease. Ann Neurol 1998 Aug; 44(2): 177–86PubMedCrossRef

61.

Trimmer PA, Borland MK, Keeney PM, et al. Parkinson’s disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem 2004 Feb; 88(4): 800–12PubMedCrossRef

62.

Sherer TB, Betarbet R, Stout AK, et al. An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 2002 Aug 15; 22(16): 7006–15PubMed

63.

Lee HJ, Shin SY, Choi C, et al. Formation and removal of alphasynuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 2002 Feb 15; 277(7): 5411–7PubMedCrossRef

64.

Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998 Apr 9; 392(6676): 605–8PubMedCrossRef

65.

Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000 May 25; 342(21): 1560–7PubMedCrossRef

66.

Hedrich K, Eskelson C, Wilmot B, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord 2004 Oct; 19(10): 1146–57PubMedCrossRef

67.

Giasson BI, Lee VM-Y. Are ubiquitination pathways central to Parkinson’s disease? Cell 2003; 114: 1–8PubMedCrossRef

68.

Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 1998 Sep; 51(3): 890–2PubMedCrossRef

69.

Hayashi S, Wakabayashi K, Ishikawa A, et al. An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 2000 Sep; 15(5): 884–8PubMedCrossRef

70.

van de Warrenburg BP, Lammens M, Lucking CB, et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 2001 Feb 27; 56(4): 555–7PubMedCrossRef

71.

Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 2001 Sep; 50(3): 293–300PubMedCrossRef

72.

Pramstaller PP, Schlossmacher MG, Jacques TS, et al. Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 2005 Sep; 58(3): 411–22PubMedCrossRef

73.

Zhang Y, Gao J, Chung KK, et al. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A 2000 Nov 21; 97(24): 13354–9PubMedCrossRef

74.

Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000 Jul; 25(3): 302–5PubMedCrossRef

75.

Ko HS, von Coelln R, Sriram SR, et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-l, leads to catecholaminergic cell death. J Neurosci 2005 Aug 31; 25(35): 7968–78PubMedCrossRef

76.

Giasson BI, Lee VM-Y. Parkin and the molecular pathways of Parkinson’s disease. Neuron 2001 Sep 27; 31(6): 885–8PubMedCrossRef

77.

Kim YS, Patel S, Lee SJ. Lack of direct role of parkin in the steady-state level and aggregation of alpha-synuclein and the clearance of pre-formed aggregates. Exp Neurol 2006 Feb; 197(2): 538–41PubMedCrossRef

78.

Miller DW, Crawley A, Gwinn-Hardy K, et al. Unaltered alphasynuclein blood levels in juvenile Parkinsonism with a parkin exon 4 deletion. Neurosci Lett 2005 Feb 21; 374(3): 189–91PubMedCrossRef

79.

von Coelln R, Thomas B, Andrabi SA, et al. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J Neurosci 2006 Apr 5; 26(14): 3685–96CrossRef

80.

Darios F, Corti O, Lucking CB, et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 2003 Mar 1; 12(5): 517–26PubMedCrossRef

81.

Goldberg MS, Fleming SM, Palacino JJ, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003 Oct 31; 278(44): 43628–35PubMedCrossRef

82.

Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci U S A 2005 Feb 8; 102(6): 2174–9PubMedCrossRef

83.

von Coelln R, Thomas B, Savitt JM, et al. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A 2004 Jul 20; 101(29): 10744–9CrossRef

84.

Palacino JJ, Sagi D, Goldberg MS, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004 Apr 30; 279(18): 18614–22PubMedCrossRef

85.

Greene JC, Whitworth AJ, Kuo I, et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 2003 Apr 1; 100(7): 4078–83PubMedCrossRef

86.

Pesah Y, Pham T, Burgess H, et al. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 2004 May; 131(9): 2183–94PubMedCrossRef

87.

Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003 Jan 10; 299(5604): 256–9PubMedCrossRef

88.

Wilson MA, Collins JL, Hod Y, et al. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson’s disease. Proc Natl Acad Sci USA 2003 Aug 5; 100(16): 9256–61PubMedCrossRef

89.

Tao X, Tong L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. J Biol Chem 2003 Aug 15; 278(33): 31372–9PubMedCrossRef

90.

Lee SJ, Kim SJ, Kim IK, et al. Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. J Biol Chem 2003 Nov 7; 278(45): 44552–9PubMedCrossRef

91.

Honbou K, Suzuki NN, Horiuchi M, et al. Crystallization and preliminary crystallographic analysis of DJ-1, a protein associated with male fertility and parkinsonism. Acta Crystallogr D Biol Crystallogr 2003 Aug; 59 (Pt 8): 1502–3PubMedCrossRef

92.

Huai Q, Sun Y, Wang H, et al. Crystal structure of DJ-l/RS and implication on familial Parkinson’s disease. FEBS Lett 2003 Aug 14; 549(1–3): 171–5PubMedCrossRef

93.

Bandyopadhyay S, Cookson MR. Evolutionary and functional relationships within the DJ1 superfamily. BMC Evol Biol 2004 Feb 19; 4: 6PubMedCrossRef

94.

Zhang L, Shimoji M, Thomas B, et al. Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 2005 Jul 15; 14(14): 2063–73PubMedCrossRef

95.

Yokota T, Sugawara K, Ito K, et al. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 2003 Dec 26; 312(4): 1342–8PubMedCrossRef

96.

Martinat C, Shendelman S, Jonason A, et al. Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-derived cell model of primary Parkinsonism. PLoS Biol 2004 Nov; 2(11): E327PubMedCrossRef

97.

Shendelman S, Jonason A, Martinat C, et al. DJ-1 is a redoxdependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2004 Nov; 2(11): E362PubMedCrossRef

98.

Hod Y, Pentyala SN, Whyard TC, et al. Identification and characterization of a novel protein that regulates RNA-protein interaction. J Cell Biochem 1999 Mar 1; 72(3): 435–44PubMedCrossRef

99.

Abou-Sleiman PM, Healy DG, Quinn N, et al. The role of pathogenic DJ-1 mutations in Parkinson’s disease. Ann Neurol 2003 Sep; 54(3): 283–6PubMedCrossRef

100.

Gorner K, Holtorf E, Odoy S, et al. Differential effects of Parkinson’s disease-associated mutations on stability and folding of DJ-1. J Biol Chem 2004 Feb 20; 279(8): 6943–51PubMedCrossRef

101.

Miller DW, Ahmad R, Hague S, et al. L166P mutant DJ-1, causative for recessive Parkinson’s disease, is degraded through the ubiquitin-proteasome system. J Biol Chem 2003 Sep 19; 278(38): 36588–95PubMedCrossRef

102.

Olzmann JA, Brown K, Wilkinson KD, et al. Familial Parkinson’s disease-associated L166P mutation disrupts DJ-1 protein folding and function. J Biol Chem 2004 Feb 27; 279(9): 8506–15PubMedCrossRef

103.

Chen L, Cagniard B, Mathews T, et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 2005 Jun 3; 280(22): 21418–26PubMedCrossRef

104.

Goldberg MS, Pisani A, Haburcak M, et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 2005 Feb 17; 45(4): 489–96PubMedCrossRef

105.

Kim RH, Smith PD, Aleyasin H, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-l,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 2005 Apr 5; 102(14): 5215–20PubMedCrossRef

106.

Meulener M, Whitworth AJ, Armstrong-Gold CE, et al. Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 2005 Sep 6; 15(17): 1572–7PubMedCrossRef

107.

Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteinesulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 2004 Jun 15; 101(24): 9103–8PubMedCrossRef

108.

Kinumi T, Kimata J, Taira T, et al. Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun 2004 May 7; 317(3): 722–8PubMedCrossRef

109.

Mitsumoto A, Nakagawa Y, Takeuchi A, et al. Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radic Res 2001 Sep; 35(3): 301–10PubMedCrossRef

110.

Valente EM, Salvi S, Ialongo T, et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 2004 Sep; 56(3): 336–41PubMedCrossRef

111.

Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 2001 Jul 27; 20(33): 4457–65PubMedCrossRef

112.

Hatano Y, Li Y, Sato K, et al. Novel PINKl mutations in earlyonset parkinsonism. Ann Neurol 2004 Sep; 56(3): 424–7PubMedCrossRef

113.

Rohe CF, Montagna P, Breedveld G, et al. Homozygous PINKl C-terminus mutation causing early-onset parkinsonism. Ann Neurol 2004 Sep; 56(3): 427–31PubMedCrossRef

114.

Ibanez P, Lesage S, Lohmann E, et al. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 2006 Mar; 129 (Pt 3): 686–94PubMedCrossRef

115.

Silvestri L, Caputo V, Bellacchio E, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 2005 Nov 15; 14(22): 3477–92PubMedCrossRef

116.

Deng H, Jankovic J, Guo Y, et al. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun 2005 Dec 2; 337(4): 1133–8PubMedCrossRef

117.

Beilina A, van der BM, Ahmad R, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A 2005 Apr 19; 102(16): 5703–8PubMedCrossRef

118.

Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006 Jun 29; 441: 1162–6CrossRef

119.

Clark IE, Dodson MW, Jiang C, et al. Drosophila pinkl is required for mitochondrial function and interacts genetically with parkin. Nature 2006 Jun 29; 441: 1157–61CrossRef

120.

Tang B, Xiong H, Sun P, et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson’s disease. Hum Mol Genet 2006 Jun 1; 15(11): 1816–25PubMedCrossRef

121.

Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004 Nov 18; 44(4): 601–7PubMedCrossRef

122.

Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004 Nov 18; 44(4): 595–600PubMedCrossRef

123.

Taylor JP, Mata IF, Farrer MJ. LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol Med 2006 Feb; 12(2): 76–82PubMedCrossRef

124.

Paisan-Ruiz C, Lang AE, Kawarai T, et al. LRRK2 gene in Parkinson disease. Neurology 2005 Sept 13; 65(5): 696–700PubMedCrossRef

125.

Deng H, Le W, Guo Y, et al. Genetic and clinical identification of Parkinson’s disease patients with LRRK2 G2019S mutation. Ann Neurol 2005 Jun; 57(6): 933–4PubMedCrossRef

126.

Gilks WP, Abou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005 Jan 29; 365(9457): 415–6PubMed

127.

Di Fonzo A, Rohe CF, Ferreira J, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005 Jan 29; 365(9457): 412–5PubMedCrossRef

128.

Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005 Apr; 76(4): 672–80PubMedCrossRef

129.

Hernandez D, Paisan RC, Crawley A, et al. The dardarin G2019S mutation is a common cause of Parkinson’s disease but not other neurodegenerative diseases. Neurosci Lett 2005 Dec 9; 389(3): 137–9PubMedCrossRef

130.

Nichols WC, Pankratz N, Hernandez D, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005 Jan 29; 365(9457): 410–2PubMed

131.

Giasson BI, Covy JP, Bonini NM, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006 Feb; 59(2): 315–22PubMedCrossRef

132.

West AB, Moore DJ, Biskup S, et al. Parkinson’s diseaseassociated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005 Nov 15; 102(46): 16842–7PubMedCrossRef

133.

Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 2005 Aug 1; 14(15): 2099–111PubMedCrossRef

134.

Tieu K, Perier C, Caspersen C, et al. D-beta-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 2003 Sep; 112(6): 892–901PubMed

Titel: Role of Mitochondrial Dysfunction in Parkinson’s Disease
Implications for Treatment
verfasst von: Chenere P. Ramsey
Dr Benoit I. Giasson
Publikationsdatum: 01.02.2007
Verlag: Springer International Publishing
Erschienen in: Drugs & Aging / Ausgabe 2/2007
Print ISSN: 1170-229X
Elektronische ISSN: 1179-1969
DOI: https://doi.org/10.2165/00002512-200724020-00002

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