References for this Review were identified by searches of MEDLINE and of Current Contents with the search terms “mitochondria”, “α-synuclein”, “proteasome”, between 2000 and 2007. References were also identified from relevant articles and through searches of the author's files. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English were reviewed.
ReviewMitochondria in the aetiology and pathogenesis of Parkinson's disease
Introduction
The incidence of Parkinson's disease (PD) is estimated as 8–18 per 100 000 person-years, and the prevalence is approximately 0·3% of the entire population: PD affects more than 1% of those older than 60 years and up to 4% of those older than 80 years.1 PD is, therefore, the second most common neurodegenerative disease after Alzheimer's disease. The clinical phenotype of PD is homogeneous, and the clinical–pathological correlation can be as high as 98·5% with experienced diagnosticians.2 However, the genotype of PD is heterogeneous, and several genes are known to cause familial PD (table), whereas other genes are associated with parkinsonian syndromes. The aetiology of the PD phenotype is, therefore, multifactorial, which is also likely to apply to most of the, apparently sporadic, idiopathic cases of PD.3 Several biochemical abnormalities that were thought to be relevant to the pathogenesis were seen in the brains of patients with PD before the discovery of the first genetic cause;4 these abnormalities included mitochondrial dysfunction, free-radical-mediated damage, excitotoxicity, and inflammatory changes. Data on the phenotype and expression of the mutant genes implicated in familial PD have confirmed the relevance of these biochemical deficits to the pathogenesis. The link between mitochondrial dysfunction and idiopathic PD was first made after the discovery of mitochondrial complex I deficiency in the substantia nigra.5 The connection between mitochondria and PD has been reinforced by the finding that several of the genes that cause familial PD encode mitochondrial proteins and that mitochondrial toxins can cause PD in animals. Apart from the production of energy substrates by oxidative phosphorylation, mitochondria have a fundamental role in mediating cell death by apoptosis, which has been reviewed in detail elsewhere.6 Many different cellular processes can lead to apoptosis through mitochondrial membrane permeabilisation, and many molecules regulate this pathway. Inevitably, many of the biochemical abnormalities caused by expression of mutant genes that are discussed in this Review might initiate mitochondrial-mediated apoptosis; however, the abnormalities will be discussed in detail only if they have a direct connection to mitochondria or mitochondrial function beyond the initiation of apoptosis. The contribution of mitochondria to the aetiology and pathogenesis of PD will be reviewed.
Section snippets
Mitochondrial dysfunction in PD
The direct relation between mitochondrial dysfunction and PD came from the post-mortem description of complex I deficiency in the substantia nigra of patients with PD.5 Subsequently, the deficiency was also seen in the skeletal muscle and platelets7, 8 and there was a decrease in complex I proteins in the substantia nigra of patients with PD.9 The complex I deficiency in the substantia nigra and platelets has been consistently detected,10, 11, 12, 13, 14 whereas the mitochondrial abnormality in
Mitochondrial DNA in patients with PD
Because the mitochondrial DNA (mtDNA) encodes 13 of the 83 respiratory chain protein subunits, including seven of the complex I proteins, mutations in the mtDNA were an obvious early target for analysis. Although there are more deletions in the mtDNA of patients with PD, a comparison with age-matched controls reported no substantial increase.20, 21, 22 However, since these early studies, more sensitive techniques have become available to detect the proportion of deleted mtDNA in individual
The gene and protein
PARK2 (parkin) is transcribed ubiquitously, and intracellular localisation studies have reported the association of parkin and the endoplasmic reticulum, Golgi apparatus, synaptic vesicles, and mitochondria.42, 43, 44 The function of parkin is unknown but the protein contains several domains for protein–protein interactions and E3 ligase activity. The ligase activity is a function of the ubiquitin proteasomal pathway, and several substrates for parkin ubiquitin ligase activity have been found,
Mitochondrial DNA polymerase gamma 1 (POLG1)
Mitochondrial DNA polymerase gamma (POLG1) is essential for mtDNA synthesis, replication, and repair. The protein is a heterodimer that comprises a 140 kDa α-subunit and a 41 kDa β-subunit, which are encoded by nuclear DNA and imported into the mitochondria where they are located within the inner mitochondrial membrane. The α-subunit is catalytic and contains polymerase and exonuclease activities; the β-subunit helps DNA binding and promotes DNA synthesis.98
Mutations in the gene encoding POLG1 (
Non-mitochondrial proteins and mitochondrial dysfunction
Mutations and multiplications of α-synuclein are a cause of autosomal dominant PD. α-Synuclein is an important component of Lewy bodies that is enriched in nerve terminals. The mechanisms by which this protein exerts its toxicity are not known but probably include enhanced aggregation; this explanation would fit with the toxicity of wild-type α-synuclein in cell models and patients with familial PD with multiplications of the gene encoding α-synuclein. Phosphorylation of the serine residue at
Mitochondrial toxins and PD
Although no toxin faithfully reproduces the clinical or pathological phenotype of PD (and there is a similar limitation for genetic models), several compounds induce dopaminergic cell death in human beings and other animals.
MPTP causes dopaminergic cell loss in the substantia nigra and induces parkinsonism in primates and rodents. MPTP is preferentially converted to MPP+ (1-methyl-4-phenylpyridinium) by monoamine oxidase B.133 MPP+ is concentrated by the mitochondria, where it inhibits complex
Mitochondrial dysfunction, oxidative stress, and the ubiquitin proteasomal system
There is substantial evidence of free-radical-mediated damage to proteins, lipids, and DNA in the substantia nigra of patients with PD,143 but the relationship between free-radical-induced damage and the complex I defect is not fully understood. However, inhibition of complex I or mutation of a complex I subunit results in increased free-radical generation; conversely, enhanced oxidative stress can induce abnormalities of mitochondrial function.144, 145 Adult nigral dopaminergic neurons are
Therapeutic implications
The recognition that mitochondrial dysfunction has a role in the pathogenesis of PD has provided a way to test the hypothesis that drugs that improve mitochondrial function might slow the progression of PD. The first of these studies used co-enzyme Q10, which functions as a component of the respiratory chain that shuttles electrons between complexes I and III and as an antioxidant. The pilot trial reported by Shults and co-workers used a double-blind, placebo-controlled design with 16–23
Conclusions
The genetic causes of PD serve to re-enforce the validity of the mitochondria–oxidative stress–proteasomal dysfunction axis in the pathogenesis of PD. Mutations and multiplications in the gene encoding α-synuclein enhance the aggregation of the protein, and this is enhanced by free radicals. Overexpression of wild-type and mutant forms of α-synuclein increase oxidative stress and lower the threshold for cell death from toxins such as dopamine and paraquat. Parkin and UCHL1 are part of the
Search strategy and selection criteria
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