Parkinson's disease is a progressive neurological disorder characterized primarily by motor symptoms that include rigidity, hypokinesia and tremor. The most pronounced neuropathological feature is a loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to a reduction in dopamine levels in the target region, the striatum. In the substantia nigra, some neurons have intracytoplasmic inclusions known as Lewy bodies.
In most patients, Parkinson's disease shows no clear inheritance and the cause of neurodegeneration is not known. Several disease mechanisms have been proposed, including oxidative stress and mitochondrial dysfunction. Some emphasis has been placed on the possibility that environmental toxins trigger these pathological changes.
In the late 1990s, the discovery of the gene that causes a rare autosomal-dominant form of Parkinson's disease led to renewed interest in the search for pathogenic mechanisms. The mutated gene encodes α-synuclein, a synaptic protein of unknown function. It has been suggested that it plays a role in the recycling of vesicles that have released their neurotransmitter content into the synaptic cleft. Moreover, further rare forms of Parkinson's disease have been identified that result from mutations in parkin and ubiquitin carboxy-terminal hydrolase L1. These proteins participate in the ubiquitin–proteasome pathway, which is responsible for the degradation of unwanted proteins.
We speculate why changes in these diverse genes lead to a neurodegenerative process that is relatively focused on dopamine-containing neurons, and emphasize the role of dopamine-dependent oxidative stress in this process. We believe that there are multiple aetiological triggers, resulting from either genetic changes or environmental insults, which share the same final common pathway to cell death in dopaminergic neurons. Increased levels of cytoplasmic dopamine in nigral neurons in Parkinson's disease patients might result in dopamine oxidation and the generation of reactive oxygen species that can damage and eventually kill these neurons.
One pathway that might lead to these events involves impaired vesicular storage of dopamine. Recent experimental evidence shows that the expression of mutant α-synuclein in a human dopaminergic cell line increases cytoplasmic dopamine levels and raises the levels of superoxide radicals in the cytoplasm.
Dopamine-induced oxidative stress, impaired synaptic vesicle function and misfolding of α-synuclein, due to mutations or to oxidative damage to this protein, might be components in a self-perpetuating vicious cycle that eventually leads to the demise of dopaminergic neurons.
Parkinson's disease is a devastating neurological condition that affects at least four million people. A striking feature of this disorder is the preferential loss of dopamine-producing neurons in the midbrain. Several aetiological triggers have been linked to Parkinson's disease, including genetic mutations and environmental toxins, but the pathway that leads to cell death is unknown. Recent developments have shed light on the pathogenic mechanisms that underlie the degeneration of these cells. We propose that defective sequestration of dopamine into vesicles, leading to the generation of reactive oxygen species in the cytoplasm, is a key event in the demise of dopaminergic neurons in Parkinson's disease, and might represent a common pathway that underlies both genetic and sporadic forms of the disorder.
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Our work described in this article was supported by grants from the US Parkinson's Disease Foundation, the Swedish Parkinson's Disease Foundation and the Swedish Research Council, and by awards from the Swedish Society for the Neurologically Handicapped and the Åke Wiberg Foundation. We thank members of the EU-funded concerted action on Early Pathogenetic Markers of Slow Neurodegenerative Diseases for fruitful discussions, M.-F. Chesselet, S. Lund, G. Paul and R. Smith for critical reading of the manuscript, and B. Mattsson for invaluable help with figures.
Encyclopedia of Life Sciences
A neurotransmitter that is characterized by a catechol ring and an alkylamine side chain; examples are dopamine, adrenaline and noradrenaline.
- OXIDATIVE STRESS
A state of imbalance between the production of reactive oxygen species and their clearance by cellular antioxidant systems.
- LEWY BODY
An electron-dense, intracytoplasmic neuronal inclusion composed of granular and filamentous material that is particularly prevalent in the brains of patients with Parkinson's disease, dementia with Lewy bodies and Lewy body disease.
The process of producing of a dense fibrous network of neuroglia; includes astrocytosis — the proliferation of astrocytes in the area of a degenerative lesion.
- PROTEIN CARBONYL
The characteristic −C=O group of aldehydes and ketones, which are derived from the direct oxidation of amino-acid side chains by reactive oxygen species. They are indicative of oxidative damage to proteins.
A reactive molecule that is formed by the spontaneous oxidation of dopamine; it can react with and covalently modify cysteinyl residues in proteins.
- LOCUS COERULEUS
A nucleus of the brainstem that is the main supplier of noradrenaline to the brain.
- RAPHE NUCLEI
A series of neuronal groups located along the midline of the brainstem. They constitute the main supply of 5-hydroxytryptamine to the rest of the brain.
- UBIQUITIN–PROTEASOME PATHWAY
A cellular system that is responsible for degrading damaged or misfolded proteins; attachment of ubiquitin molecules to lysine residues in a given protein targets it for destruction by a multi-enzyme complex known as the proteasome.
An intermediate species resembling an elongated filament that is formed in the fibrillization process from monomer to fibril.
- RESERVE POOL
A population of vesicles distal to the active zone that is recruited during periods of high-frequency stimulation.
- ISCHAEMIC PRECONDITIONING
A phenomenon whereby a brief interruption of blood supply to the brain protects the tissue from a subsequent ischaemic episode.
- PC12 CELLS
Neuron-like cells that are derived from a malignant neural crest tumour (a phaeochromocytoma).
- ADAPTOR MOLECULE
A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.
- ANTISENSE OLIGONUCLEOTIDE
An RNA sequence complementary to the messenger RNA of a given gene that can hybridize to this piece of RNA, thereby blocking its translation into protein.
- ACTIVE ZONE
A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.
- READILY RELAEASABLE POOL
The pool of synaptic vesicles that is available for rapid fusion with the presynaptic membrane in response to the arrival of a nerve impulse. These vesicles are docked to the membrane and have been biochemically primed for release.
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Lotharius, J., Brundin, P. Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein. Nat Rev Neurosci 3, 932–942 (2002). https://doi.org/10.1038/nrn983
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