Key Points
-
Parkinson's disease is the most common neurodegenerative movement disorder, affecting ∼1% of the population above the age of 60. Its pathological hallmarks are the preferential loss of dopaminergic neurons of the substantia nigra pars compacta and formation of Lewy bodies — intracytoplasmic inclusion bodies that are mainly composed of fibrillar α-synuclein.
-
Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson's disease, as inhibition of complex I of the mitochondrial electron transport chain and oxidative stress result in dopaminergic cell loss and parkinsonism in vivo.
-
A minority of Parkinson's disease cases are familial, and these have been used to identify 5 genes, α-synuclein, parkin, DJ1 (Parkinson's disease (autosomal recessive, early onset) 7), PINK1 (phosphatase and tensin homologue (PTEN)-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2) that are causal of the disease. Recently, mutations in a sixth gene, HtrA serine peptidase 2 (HTRA2, also known as OMI) have also been tentatively associated with Parkinson's disease.
-
We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.
-
While α-synuclein and parkin mutations indicate that protein misfolding and the ubiquitin–proteasome system (UPS) dysfunction are part of a significant upstream pathway en route to dopaminergic degeneration, the discovery of PINK1, DJ-1 and OMI/HTRA2 mutations confirm that mitochondrial dysfunction is another principle upstream pathway that leads to parkinsonism. As there is considerable crosstalk between these systems, an intriguing question is whether all the known genes converge to a common pathogenetic pathway.
-
The mechanism of how mitochondrial and proteasomal impairment lead to dopamine cell loss is becoming clearer, and the generation of oxidative stress might be common to both. Evidence of increased oxidative damage after mitochondrial or proteasomal impairment has been shown in vivo.
-
There are at least two possible mechanisms: mitochondrial dysfunction that leads to ATP depletion, and oxidative stress that causes UPS dysfunction. Conversely, UPS deregulation results in secondary mitochondrial dysfunction and damage.
-
We discuss how these pathways conspire to cause cell death in Parkinson's disease.
Abstract
The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The α-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997). The first study to show α-synuclein in Lewy bodies, linking synuclein biology and dysfunction to sporadic PD.
Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K. & Seitelberger, F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 20, 415–455 (1973).
Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983). The first major study to show that MPTP can induce parkinsonism in humans.
Nicklas, W. J., Vyas, I. & Heikkila, R. E. 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 Sci. 36, 2503–2508 (1985).
Fiskum, G., Starkov, A., Polster, B. M. & Chinopoulos, C. Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease. Ann. NY Acad. Sci. 991, 111–119 (2003).
Mizuno, Y. et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem. Biophys. Res. Commun. 163, 1450–1455 (1989).
Parker, W. D. Jr, Boyson, S. J. & Parks, J. K. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann. Neurol. 26, 719–723 (1989).
Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1, 1269 (1989). The first study to show complex I deficiency in the brains of patients with PD, linking the MPTP model to sporadic PD.
Orth, M. & Schapira, A. H. Mitochondrial involvement in Parkinson's disease. Neurochem. Int. 40, 533–541 (2002).
Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000). Reports perhaps the best animal model of PD — parkinsonism in rats caused by the complex I inhibitor rotenone.
Thyagarajan, D. et al. A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann. Neurol. 48, 730–736 (2000).
Luoma, P. et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study. Lancet 364, 875–882 (2004).
Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997). The first report of a single gene mutation resulting in PD.
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Conway, K. A., Rochet, J. C., Bieganski, R. M. & Lansbury, P. T. Jr. Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct. Science 294, 1346–1349 (2001). An important paper showing that dopamine modulates α-synuclein aggregation, which suggests a mechanism for the regional selectivity of PD.
Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003).
Valente, E. M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004). The first report of a PD gene unequivocally localized to mitochondria.
Leroy, E. et al. The ubiquitin pathway in Parkinson's disease. Nature 395, 451–452 (1998).
Strauss, K. M. et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14, 2099–2111 (2005).
Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123, 383–396 (2005). A groundbreaking study that suggests a role for α-synuclein in the prevention of neurodegeneration.
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998).
Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nature Med. 4, 1318–1320 (1998).
Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).
Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).
Miller, D. W. et al. α-Synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62, 1835–1838 (2004).
Farrer, M. et al. α-Synuclein gene haplotypes are associated with Parkinson's disease. Hum. Mol. Genet. 10, 1847–1851 (2001).
Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biol. 4, 160–164 (2002). An important study showing that phosphorylation of synuclein at Ser129 may mediate pathogenicity of synuclein in vivo.
Chen, L. & Feany, M. B. α-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nature Neurosci. 8, 657–663 (2005).
Feany, M. B. & Bender, W. W. A Drosophila model of Parkinson's disease. Nature 404, 394–398 (2000).
Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).
Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002).
Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA 99, 8968–8973 (2002).
Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).
Lo Bianco, C. et al. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease. Proc. Natl Acad. Sci. USA 101, 17510–17515 (2004).
Oluwatosin-Chigbu, Y. et al. Parkin suppresses wild-type α-synuclein-induced toxicity in SHSY-5Y cells. Biochem. Biophys. Res. Commun. 309, 679–684 (2003).
Goedert, M. α-Synuclein and neurodegenerative diseases. Nature Rev. Neurosci. 2, 492–501 (2001).
Orth, M. & Tabrizi, S. J. Models of Parkinson's disease. Mov. Disord. 18, 729–737 (2003).
Tabrizi, S. J. et al. Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity. Hum. Mol. Genet. 9, 2683–2689 (2000).
Dauer, W. et al. Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc. Natl Acad. Sci. USA 99, 14524–14529 (2002).
Klivenyi, P. et al. Mice lacking α-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. 17 Nov 2005 (10.1016/j.nbd.2005.08.018).
Sulzer, D. et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc. Natl Acad. Sci. USA 97, 11869–11874 (2000).
Abbas, N. et al. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. Hum. Mol. Genet. 8, 567–574 (1999).
Lucking, C. B. et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group. N. Engl. J. Med. 342, 1560–1567 (2000).
Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin–protein ligase. Nature Genet. 25, 302–305 (2000).
Sakata, E. et al. Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin–like domain. EMBO Rep. 4, 301–306 (2003).
Ciechanover, A. The ubiquitin–proteasome pathway: on protein death and cell life. EMBO J. 17, 7151–1760 (1998).
Farrer, M. et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 50, 293–300 (2001).
Muftuoglu, M. et al. Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov. Disord. 19, 544–548 (2004).
Shimura, H. et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann. Neurol. 45, 668–672 (1999).
Schlossmacher, M. G. et al. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am. J. Pathol. 160, 1655–1667 (2002).
Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003). The first study to link parkin to mitochondrial dysfunction.
Greene, J. C., Whitworth, A. J., Andrews, L. A., Parker, T. J. & Pallanck, L. J. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum. Mol. Genet. 14, 799–811 (2005).
Whitworth, A. J. et al. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl Acad. Sci. USA 102, 8024–8029 (2005).
Palacino, J. J. et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614–18622 (2004).
Goldberg, M. S. et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278, 43628–43635 (2003).
Itier, J. M. et al. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum. Mol. Genet. 12, 2277–2291 (2003).
Perez, F. A. & Palmiter, R. D. Parkin-deficient mice are not a robust model of parkinsonism. Proc. Natl Acad. Sci. USA 102, 2174–2179 (2005).
Khan, N. L. et al. Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125, 2248–2256 (2002).
Darios, F. et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum. Mol. Genet. 12, 517–526 (2003).
Casellas, P., Galiegue, S. & Basile, A. S. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem. Int. 40, 475–486 (2002).
Zhaung, Z. P. & McCauley, R. Ubiquitin is involved in the in vitro insertion of monoamine oxidase B into mitochondrial outer membranes. J. Biol. Chem. 264, 14594–14596 (1989).
Takahashi, R., Imai, Y., Hattori, N. & Mizuno, Y. Parkin and endoplasmic reticulum stress. Ann. NY Acad. Sci. 991, 101–106 (2003).
Yamanaka, K. et al. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nature Cell Biol. 5, 336–340 (2003).
Hyun, D. H., Lee, M., Halliwell, B. & Jenner, P. Effect of overexpression of wild-type or mutant parkin on the cellular response induced by toxic insults. J. Neurosci. Res. 82, 232–244 (2005).
Chung, K. K. et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304, 1328–1331 (2004).
Yao, D. et al. Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc. Natl Acad. Sci. USA 101, 10810–10814 (2004).
LaVoie, M. J., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G. & Selkoe, D. J. Dopamine covalently modifies and functionally inactivates parkin. Nature Med. 11, 1214–1221 (2005). An important study showing that parkin activity is inactivated by dopamine, which suggests a mechanism for parkin dysfunction in sporadic PD.
Wang, C. et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. Hum. Mol. Genet. 14, 3885–3897 (2005).
Kalia, S. K. et al. BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron 44, 931–945 (2004).
Robinson, P. A. & Ardley, H. C. Ubiquitin–protein ligases. J. Cell Sci. 117, 5191–5194 (2004).
von Coelln, R., Dawson, V. L. & Dawson, T. M. Parkin-associated Parkinson's disease. Cell Tissue Res. 318, 175–184 (2004).
Dong, Z. et al. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc. Natl Acad. Sci. USA 100, 12438–12443 (2003).
Yang, Y., Nishimura, I., Imai, Y., Takahashi, R. & Lu, B. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37, 911–924 (2003).
Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001).
Choi, P. et al. SEPT5_v2 is a parkin-binding protein. Brain Res. Mol. Brain Res. 117, 179–189 (2003).
Ko, H. S. et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J. Neurosci. 25, 7968–7978 (2005).
Petrucelli, L. et al. Parkin protects against the toxicity associated with mutant α-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36, 1007–1019 (2002).
Shimura, H. et al. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293, 263–269 (2001).
Abou-Sleiman, P. M., Healy, D. G., Quinn, N., Lees, A. J. & Wood, N. W. The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann. Neurol. 54, 283–286 (2003).
Rizzu, P. et al. DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia. Ann. Neurol. 55, 113–118 (2004).
Bandopadhyay, R. et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain 127, 420–430 (2004).
Junn, E. et al. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc. Natl Acad. Sci. USA 102, 9691–9696 (2005).
Zhang, L. et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum. Mol. Genet. 14, 2063–2073 (2005).
Cookson, M. R. The biochemistry of Parkinson's disease. Annu. Rev. Biochem. 74, 29–52 (2005).
Nagakubo, D. et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem. Biophys. Res. Commun. 231, 509–513 (1997).
Hod, Y., Pentyala, S. N., Whyard, T. C. & El-Maghrabi, M. R. Identification and characterization of a novel protein that regulates RNA–protein interaction. J. Cell Biochem. 72, 435–444 (1999).
Mitsumoto, A. & Nakagawa, Y. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic. Res. 35, 885–893 (2001).
Canet-Aviles, R. M. et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA 101, 9103–9108 (2004).
Yang, Y. et al. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc. Natl Acad. Sci. USA 102, 13670–13675 (2005).
Meulener, M. et al. Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Curr. Biol. 15, 1572–1577 (2005).
Yokota, T. et al. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem. Biophys. Res. Commun. 312, 1342–1348 (2003).
Kim, R. H. et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl Acad. Sci. USA 102, 5215–5220 (2005).
Kim, R. H. et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005).
Xu, J. et al. The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum. Mol. Genet. 14, 1231–1241 (2005).
Shinbo, Y., Taira, T., Niki, T., Iguchi-Ariga, S. M. & Ariga, H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. Int. J. Oncol. 26, 641–648 (2005).
Honbou, K. et al. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J. Biol. Chem. 278, 31380–31384 (2003).
Tao, X. & Tong, L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease. J. Biol. Chem. 278, 31372–31379 (2003).
Wilson, M. A., Collins, J. L., Hod, Y., Ringe, D. & Petsko, G. A. The 1.1-Å resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Proc. Natl Acad. Sci. USA 100, 9256–9261 (2003).
Miller, D. W. et al. L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin–proteasome system. J. Biol. Chem. 278, 36588–36595 (2003).
Macedo, M. G. et al. The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes. Hum. Mol. Genet. 12, 2807–2816 (2003).
Moore, D. J., Zhang, L., Dawson, T. M. & Dawson, V. L. A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization. J. Neurochem. 87, 1558–1567 (2003).
Shendelman, S., Jonason, A., Martinat, C., Leete, T. & Abeliovich, A. DJ-1 is a redox-dependent molecular chaperone that inhibits α-synuclein aggregate formation. PLoS Biol. 2, e362 (2004).
Unoki, M. & Nakamura, Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20, 4457–4465 (2001).
Nakajima, A., Kataoka, K., Hong, M., Sakaguchi, M. & Huh, N. H. BRPK, a novel protein kinase showing increased expression in mouse cancer cell lines with higher metastatic potential. Cancer Lett. 201, 195–201 (2003).
Silvestri, L. et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum. Mol. Genet. 14, 3477–3492 (2005).
Rogaeva, E. et al. Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. Arch. Neurol. 61, 1898–1904 (2004).
Bonifati, V. et al. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65, 87–95 (2005).
Beilina, A. et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl Acad. Sci. USA 102, 5703–5708 (2005).
Li, Y. et al. Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism. Neurology 64, 1955–1957 (2005).
Chacinska, A., Pfanner, N. & Meisinger, C. How mitochondria import hydrophilic and hydrophobic proteins. Trends Cell Biol. 12, 299–303 (2002).
Hanks, S. K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).
Petit, A. et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson's disease-related mutations. J. Biol. Chem. 280, 34025–34032 (2005).
Schulenberg, B., Aggeler, R., Beechem, J. M., Capaldi, R. A. & Patton, W. F. Analysis of steady-state protein phosphorylation in mitochondria using a novel fluorescent phosphosensor dye. J. Biol. Chem. 278, 27251–27255 (2003).
Chen, R., Fearnley, I. M., Peak-Chew, S. Y. & Walker, J. E. The phosphorylation of subunits of complex I from bovine heart mitochondria. J. Biol. Chem. 279, 26036–26045 (2004).
Kokoszka, J. E. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004).
Gray, C. W. et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267, 5699–5710 (2000).
Park, H. J., Seong, Y. M., Choi, J. Y., Kang, S. & Rhim, H. Alzheimer's disease-associated amyloid β interacts with the human serine protease HtrA2/Omi. Neurosci. Lett. 357, 63–67 (2004).
Martins, L. M. et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell Biol. 24, 9848–9862 (2004).
Paisan-Ruiz, C. et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595–600 (2004).
Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).
Gilks, W. P. et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415–416 (2005).
West, A. B. et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA 102, 16842–16847 (2005).
Gloeckner, C. J. et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15, 223–232 (2005).
Smith, W. W. et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl Acad. Sci. USA 102, 18676–18681 (2005).
Tatton, W. G., Chalmers-Redman, R., Brown, D. & Tatton, N. Apoptosis in Parkinson's disease: signals for neuronal degradation. Ann. Neurol. 53 (Suppl. 3), S61–S70; discussion S70–S72 (2003).
Vila, M. & Przedborski, S. Targeting programmed cell death in neurodegenerative diseases. Nature Rev. Neurosci. 4, 365–375 (2003).
Bowling, A. C. & Beal, M. F. Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci. 56, 1151–1171 (1995).
Jazwinski, S. M. Genetics of longevity. Exp. Gerontol. 33, 773–783 (1998).
Khalyavkin, A. V. & Yashin, A. I. How the analysis of genetic mutations can help us to solve basic problems in gerontology? II. Life extending genetic modifications in budding yeast S. cereviseae, fruit fly D. melanogaster and laboratory mice M. musculus. Adv. Gerontol. 12, 46–56 (2003).
Hoglinger, G. U. et al. Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease. J. Neurochem. 86, 1297–1307 (2003).
Sullivan, P. G. et al. Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover. J. Biol. Chem. 279, 20699–20707 (2004).
Beal, M. F. Limited-time exposure to mitochondrial toxins may lead to chronic progressive neurodegenerative diseases. Mov. Disord. 15, 434–535 (2000).
McNaught, K. S., Perl, D. P., Brownell, A. L. & Olanow, C. W. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann. Neurol. 56, 149–162 (2004).
Shamoto-Nagai, M. et al. An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. J. Neurosci. Res. 74, 589–597 (2003).
Qiu, J. H. et al. Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J. Neurosci. 20, 259–265 (2000).
Tanaka, Y. et al. Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 10, 919–926 (2001).
Jesenberger, V. & Jentsch, S. Deadly encounter: ubiquitin meets apoptosis. Nature Rev. Mol. Cell Biol. 3, 112–121 (2002).
Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).
Moore, D. J. et al. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. 14, 71–84 (2005).
Nicholls, D. G. Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int. J. Biochem. Cell Biol. 34, 1372–1381 (2002).
Duchen, M. R. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol. Aspects Med. 25, 365–451 (2004).
Acknowledgements
The authors gratefully acknowledge grants from the Medical Research Council (P.M.A.-S. and N.W.W.) and the Parkinson's Disease Society (N.W.W.), and a clinical training fellowship to M.M.K.M., also provided by the Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Complex I
-
Reduced NADH–ubiquinone reductase is an enzyme complex consisting of more than 40 polypeptides that spans the inner mitochondrial membrane. It oxidizes NADH, resulting in the transfer of electrons from NADH to ubiquinone.
- Mitochondrial electron transport chain
-
A collective term describing the mitochondrial enzymes (also known as complexes I–IV) that are needed to generate the electron and proton 'gradient' that is used by complex V to generate ATP.
- Dopamine transporter
-
(DAT). A monoamine transporter, the function of which is the clearance of the neurotransmitter dopamine out of a synapse into a presynaptic neuron or a glial cell.
- Complex I deficiency
-
A reduction in the enzymatic activity of complex I compared with the remaining respiratory chain complexes, as determined by in vitro biochemical assays.
- Autosomal recessive PD
-
(ARPD). A familial form of PD with an autosomal recessive mode of inheritance.
- RING finger proteins
-
Specialized zinc finger proteins that bind two atoms of zinc. Proteins containing RING fingers are involved in mediating protein–protein interactions.
- 26S proteasome
-
Macromolecules composed of many subunits that are involved in the degradation of proteins.
- ThiJ/PfpI/DJ1 superfamily
-
Proteins that share sequence homology to the bacterial ThiJ domain. Functions include protein chaperones, catalases, proteases and ThiJ kinases.
- pI
-
(Isoelectric point). The pH of a solution at which a dissolved charged molecule has no electric charge and will therefore not move in an electric field.
- Mitochondrial membrane potential
-
(Δψm). A chemiosmotic gradient of protons across the inner mitochondrial membrane. The energy this creates is used for ATP synthesis by the electron transport chain.
- WD40 repeats
-
Short (∼40) amino acid motifs that form beta-propeller structures, which are thought to serve as rigid scaffolds for protein interactions. WD40 repeat-containing proteins can therefore coordinate the assembly of multi-protein complexes.
Rights and permissions
About this article
Cite this article
Abou-Sleiman, P., Muqit, M. & Wood, N. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7, 207–219 (2006). https://doi.org/10.1038/nrn1868
Issue Date:
DOI: https://doi.org/10.1038/nrn1868
This article is cited by
-
Neuropathogenesis-on-chips for neurodegenerative diseases
Nature Communications (2024)
-
SNHG14 Elevates NFAT5 Expression Through Sequestering miR-375-3p to Promote MPP + -Induced Neuronal Apoptosis, Inflammation, and Oxidative Stress in Parkinson’s Disease
Neurochemical Research (2024)
-
Orientin Modulates Nrf2-ARE, PI3K/Akt, JNK-ERK1/2, and TLR4/NF-kB Pathways to Produce Neuroprotective Benefits in Parkinson's Disease
Neurochemical Research (2024)
-
MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson’s disease
Molecular Neurodegeneration (2023)
-
Purple pitanga extract (Eugenia uniflora) attenuates oxidative stress induced by MPTP
Metabolic Brain Disease (2023)