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  • Review Article
  • Published:

Expanding insights of mitochondrial dysfunction in Parkinson's disease

Nature Reviews Neuroscience volume 7, pages 207–219 (2006)Cite this article

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.

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Figure 1: Schematic representation of the mitochondrial electron transport system.
Figure 2: Hypothetical schematic of the mitochondrial permeability transition pore.
Figure 3: Pathways to parkinsonism.

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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.

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Authors and Affiliations

  1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Patrick M. Abou-Sleiman, Miratul M. K. Muqit & Nicholas W. Wood

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  1. Patrick M. Abou-Sleiman
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  2. Miratul M. K. Muqit
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Correspondence to Nicholas W. Wood.

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DATABASES

OMIM

Parkinson's disease

FURTHER INFORMATION

The Institute of Neurology

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.

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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

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