The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD. 1. Introduction Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population above the age of 60. The classical form of the disease is characterized clinically by rigidity, resting tremor, bradykinesia, and postural instability. In addition to these four cardinal symptoms, many nonmotor symptoms frequently appear in PD, such as cognitive impairment, hallucinations, delusion, behavioral abnormalities, depression, disturbances of sleep and wakefulness, loss of smell, pain, and autonomic dysfunctions such as constipation, hypotension, urinary frequency, impotence, and sweating. The pathological hallmarks of PD are the preferential loss of dopaminergic neurons of the substantia nigra (SN) pars compacta and formation of Lewy bodies. Exposure to environmental factors inducing mitochondrial toxin like1-methyl-4-phynyl-tetrahydropyridine (MPTP) produces selective degeneration of dopaminergic neurons in SN and results in an irreversible Parkinsonism [1–3]. The active metabolite of MPTP, 1-methyl-4-phenylpyridinium ion (MPP+), is an inhibitor of complex I, and it accumulates in dopaminergic neurons because it is actively transported via dopamine transporter (DAT) [4–6]. The inhibition of the electron transport induces oxidative damage by increasing the formation of reactive oxygen species (ROS) and leads to further mitochondrial dysfunction [7]. These findings were supported by evidence
References
[1]
G. C. Davis, A. C. Williams, S. P. Markey, et al., “Chronic parkinsonism secondary to intravenous injection of meperidine analogues,” Psychiatry Research, vol. 1, no. 3, pp. 249–254, 1979.
[2]
J. W. Langston, P. Ballard, J. W. Tetrud, and I. Irwin, “Chronic parkinsonism in humans due to a product of meperidine-analog synthesis,” Science, vol. 219, no. 4587, pp. 979–980, 1983.
[3]
R. S. Burns, C. C. Chiueh, S. Markey, M. H. Ebert, D. Jakobowicz, and I. J. Kopin, “A primate model of Parkinson's disease, selective destruction of substantianigra, pars compactadopaminergic neurons by N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 80, pp. 4546–4550, 1983.
[4]
W. J. Nicklas, I. Vyas, and R. E. Heikkila, “Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine,” Life Sciences, vol. 36, no. 26, pp. 2503–2508, 1985.
[5]
R. R. Ramsay, J. I. Salach, J. Dadgar, and T. P. Singer, “Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism,” Biochemical and Biophysical Research Communications, vol. 135, no. 1, pp. 269–275, 1986.
[6]
Y. Mizuno, T. Saitoh, and N. Sone, “Inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity by 1-methyl-4-phenylpyridinium ion,” Biochemical and Biophysical Research Communications, vol. 143, no. 1, pp. 294–299, 1987.
[7]
G. Fiskum, A. Starkov, B. M. Polster, and C. Chinopoulos, “Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease,” Annals of the New York Academy of Sciences, vol. 991, pp. 111–119, 2003.
[8]
D. T. Dexter, C. J. Carter, F. R. Wells et al., “Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease,” Journal of Neurochemistry, vol. 52, no. 2, pp. 381–389, 1989.
[9]
E. Sofic, K. W. Lange, K. Jellinger, and P. Riederer, “Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease,” Neuroscience Letters, vol. 142, no. 2, pp. 128–130, 1992.
[10]
A. Yoritaka, N. Hattori, K. Uchida, M. Tanaka, E. R. Stadtman, and Y. Mizuno, “Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 7, pp. 2696–2701, 1996.
[11]
H. Shimura-Miura, N. Hattori, D. Kang, K. I. Miyako, Y. Nakabeppu, and Y. Mizuno, “Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in Parkinson's disease,” Annals of Neurology, vol. 46, no. 6, pp. 920–924, 1999.
[12]
Y. Mizuno, S. Ohta, M. Tanaka, et al., “Deficiencies in complex I subunits of the respiratory chain in Parkinson 's disease,” Biochemical and Biophysical Research Communications, vol. 163, pp. 1450–1455, 1989.
[13]
A. H. V. Schapira, J. M. Cooper, D. Dexter, P. Jenner, J. B. Clark, and C. D. Marsden, “Mitochondrial complex I deficiency in Parkinson's disease,” The Lancet, vol. 1, no. 8649, p. 1269, 1989.
[14]
R. Betarbet, T. B. Sherer, G. MacKenzie, M. Garcia-Osuna, A. V. Panov, and J. T. Greenamyre, “Chronic systemic pesticide exposure reproduces features of Parkinson's disease,” Nature Neuroscience, vol. 3, no. 12, pp. 1301–1306, 2000.
[15]
M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation in the alpha-synuclein gene identified in families with Parkinson's disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997.
[16]
R. Krüger, W. Kuhn, T. Müller et al., “Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease,” Nature Genetics, vol. 18, no. 2, pp. 106–108, 1998.
[17]
J. J. Zarranz, J. Alegre, J. C. Gómez-Esteban et al., “The new mutation, E46K, of alpha-synuclein causes Parkinson and lewy body dementia,” Annals of Neurology, vol. 55, no. 2, pp. 164–173, 2004.
[18]
M. C. Chartier-Harlin, J. Kachergus, C. Roumier et al., “Alpha-synuclein locus duplication as a cause of familial Parkinson's disease,” The Lancet, vol. 364, no. 9440, pp. 1167–1169, 2004.
[19]
P. Ibá？ez, A. M. Bonnet, B. Débarges et al., “Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease,” The Lancet, vol. 364, no. 9440, pp. 1169–1171, 2004.
[20]
K. Nishioka, S. Hayashi, M. J. Farrer et al., “Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease,” Annals of Neurology, vol. 59, no. 2, pp. 298–309, 2006.
[21]
J. Fuchs, C. Nilsson, J. Kachergus et al., “Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication,” Neurology, vol. 68, no. 12, pp. 916–922, 2007.
[22]
A. B. Singleton, M. Farrer, J. Johnston, et al., “alpha-Synuclein locus triplication causes Parkinson 's disease,” Science, vol. 302, no. 5646, p. 841, 2003.
[23]
M. Farrer, J. Kachergus, L. Forno, et al., “Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications,” Annals of Neurology, vol. 55, pp. 174–179, 2004.
[24]
W. Dauer, N. Kholodilov, M. Vila et al., “Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 22, pp. 14524–14529, 2002.
[25]
V. Bonifati, P. Rizzu, F. Squitieri et al., “DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism,” Neurological Sciences, vol. 24, no. 3, pp. 159–160, 2003.
[26]
R. M. Canet-Avilés, M. A. Wilson, D. W. Miller et al., “The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 24, pp. 9103–9108, 2004.
[27]
A. Mitsumoto and Y. Nakagawa, “DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin,” Free Radical Research, vol. 35, no. 6, pp. 885–893, 2001.
[28]
T. Taira, S. M. M. Iguchi-Ariga, and H. Ariga, “Co-localization with DJ-1 is essential for the androgen receptor to exert its transcription activity that has been impaired by androgen antagonists,” Biological and Pharmaceutical Bulletin, vol. 27, no. 4, pp. 574–577, 2004.
[29]
L. Zhang, M. Shimoji, B. Thomas et al., “Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis,” Human Molecular Genetics, vol. 14, no. 14, pp. 2063–2073, 2005.
[30]
E. Junn, W. H. Jang, X. Zhao, B. S. Jeong, and M. M. Mouradian, “Mitochondrial localization of DJ-1 leads to enhanced neuroprotection,” Journal of Neuroscience Research, vol. 87, no. 1, pp. 123–129, 2009.
[31]
R. H. Kim, P. D. Smith, H. Aleyasin et al., “Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyrindine (MPTP) and oxidative stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 14, pp. 5215–5220, 2005.
[32]
B. Thomas, R. von Coelln, A. S. Mandir, et al., “MPTP and DSP-4 susceptibility of substantianigra and locus coeruleuscatecholaminergic neurons in mice is independent of parkin activity,” Neurobiology of Disease, vol. 26, pp. 312–322, 2007.
[33]
C. Wang, H. S. Ko, B. Thomas et al., “Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function,” Human Molecular Genetics, vol. 14, no. 24, pp. 3885–3897, 2005.
[34]
N. Hattori, H. Matsumine, T. Kitada, et al., “Molecular analysis of a novel ubiquitin-like protein (PARKIN) gene in Japanese families with AR-JP:, evidence of homozygous deletions in the PARKIN gene in affected individuals,” Annals of Neurology, vol. 44, pp. 935–941, 1998.
[35]
N. Abbas, C. B. Lücking, C. Ricard, et al., “A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe,” Human Molecular Genetics, vol. 8, pp. 567–574, 1999.
[36]
M. Kann, H. Jacobs, K. Mohrmann, et al., “Role of parkin mutations in 111 community-based patients with early onset parkinsonism,” Annals of Neurology, vol. 51, pp. 621–625, 2002.
[37]
N. L. Khan, E. Graham, P. Critchley et al., “Parkin disease: a phenotypic study of a large case series,” Brain, vol. 126, no. 6, pp. 1279–1292, 2003.
[38]
K. Hedrich, C. Eskelson, B. Wilmot et al., “Distribution, type and origin of Parkin mutations: review and case studies,” Movement Disorders, vol. 19, no. 10, pp. 1146–1157, 2004.
[39]
E. M. Valente, A. R. Bentivoglio, P. H. Dixon et al., “Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36,” American Journal of Human Genetics, vol. 68, no. 4, pp. 895–900, 2001.
[40]
E. M. Valente, P. M. Abou-Sleiman, V. Caputo et al., “Hereditary early-onset Parkinson's disease caused by mutations in PINK1,” Science, vol. 304, no. 5674, pp. 1158–1160, 2004.
[41]
Y. Hatano, Y. Li, K. Sato et al., “Novel PINK1 mutations in early-onset parkinsonism,” Annals of Neurology, vol. 56, no. 3, pp. 424–427, 2004.
[42]
D. G. Healy, P. M. Abou-Sleiman, J. M. Gibson et al., “PINK1 (PARK6) associated Parkinson disease in Ireland,” Neurology, vol. 63, no. 8, pp. 1486–1488, 2004.
[43]
C. F. Rohé, P. Montagna, G. Breedveld, P. Cortelli, B. A. Oostra, and V. Bonifati, “Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism,” Annals of Neurology, vol. 56, no. 3, pp. 427–431, 2004.
[44]
Y. Li, H. Tomiyama, K. Sato et al., “Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism,” Neurology, vol. 64, no. 11, pp. 1955–1957, 2005.
[45]
J. W. Pridgeon, J. A. Olzmann, L. S. Chin, and L. Li, “PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1,” PLoS Biology, vol. 5, no. 7, article e173, 2007.
[46]
N. Exner, B. Treske, D. Paquet et al., “Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin,” Journal of Neuroscience, vol. 27, no. 45, pp. 12413–12418, 2007.
[47]
M. E. Haque, K. J. Thomas, C. D'Souza et al., “Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1716–1721, 2008.
[48]
A. Wood-Kaczmar, S. Gandhi, Z. Yao et al., “PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons,” PLoS ONE, vol. 3, no. 6, Article ID e2455, 2008.
[49]
J. C. Greene, A. J. Whitworth, I. Kuo, L. A. Andrews, M. B. Feany, and L. J. Pallanck, “Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 4078–4083, 2003.
[50]
J. Park, S. B. Lee, S. Lee et al., “Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin,” Nature, vol. 441, no. 7097, pp. 1157–1161, 2006.
[51]
I. E. Clark, M. W. Dodson, C. Jiang et al., “Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin,” Nature, vol. 441, no. 7097, pp. 1162–1166, 2006.
[52]
C. T. Chu, “Tickled PINK1: mitochondrial homeostasis and autophagy in recessive Parkinsonism,” Biochimica et Biophysica Acta, vol. 1802, no. 1, pp. 20–28, 2010.
[53]
S. Geisler, K. M. Holmstr？m, D. Skujat et al., “PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1,” Nature Cell Biology, vol. 12, no. 2, pp. 119–131, 2010.
[54]
S. Kawajiri, S. Saiki, S. Sato et al., “PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy,” FEBS Letters, vol. 584, no. 6, pp. 1073–1079, 2010.
[55]
N. Matsuda, S. Sato, K. Shiba et al., “PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy,” Journal of Cell Biology, vol. 189, no. 2, pp. 211–221, 2010.
[56]
D. Narendra, A. Tanaka, D. F. Suen, and R. J. Youle, “Parkin is recruited selectively to impaired mitochondria and promotes their autophagy,” Journal of Cell Biology, vol. 183, no. 5, pp. 795–803, 2008.
[57]
D. P. Narendra, S. M. Jin, A. Tanaka et al., “PINK1 is selectively stabilized on impaired mitochondria to activate Parkin,” PLoS Biology, vol. 8, no. 1, Article ID e1000298, 2010.
[58]
C. Vives-Bauza, C. Zhou, Y. Huang et al., “PINK1-dependent recruitment of Parkin to mitochondria in mitophagy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 1, pp. 378–383, 2010.
[59]
A. Beilina, M. Van Der Brug, R. Ahmad et al., “Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 16, pp. 5703–5708, 2005.
[60]
S. Takatori, G. Ito, and T. Iwatsubo, “Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1,” Neuroscience Letters, vol. 430, no. 1, pp. 13–17, 2008.
[61]
Y. Kim, J. Park, S. Kim et al., “PINK1 controls mitochondrial localization of Parkin through direct phosphorylation,” Biochemical and Biophysical Research Communications, vol. 377, no. 3, pp. 975–980, 2008.
[62]
C. Zhou, Y. Huang, Y. Shao et al., “The kinase domain of mitochondrial PINK1 faces the cytoplasm,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 12022–12027, 2008.
[63]
C. H. Sim, D. S. S. Lio, S. S. Mok et al., “C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1,” Human Molecular Genetics, vol. 15, no. 21, pp. 3251–3262, 2006.
[64]
Y. Yang, Y. Ouyang, L. Yang et al., “Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 19, pp. 7070–7075, 2008.
[65]
C. A. Gautier, T. Kitada, and J. Shen, “Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 32, pp. 11364–11369, 2008.
[66]
T. Amo, S. Sato, S. Saiki et al., “Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects,” Neurobiology of Disease, vol. 41, no. 1, pp. 111–118, 2011.
[67]
M. Shamoto-Nagai, W. Maruyama, Y. Kato et al., “An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells,” Journal of Neuroscience Research, vol. 74, no. 4, pp. 589–597, 2003.
[68]
W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003.
[69]
V. Jackson-Lewis and S. Przedborski, “Protocol for the MPTP mouse model of Parkinson's disease,” Nature Protocols, vol. 2, no. 1, pp. 141–151, 2007.
[70]
J. Q. Trojanowski, “Rotenone neurotoxicity: a new window on environmental causes of Parkinson's disease and related brain amyloidoses,” Experimental Neurology, vol. 179, no. 1, pp. 6–8, 2003.
