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  • Review Article
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Genetics of Parkinson disease: paradigm shifts and future prospects

Nature Reviews Genetics volume 7, pages 306–318 (2006)Cite this article

Key Points

  • Parkinson disease (PD) is the second most prevalent, age-associated, neurodegenerative disorder after Alzheimer disease.

  • PD is the major cause of parkinsonism, the clinical features of which include resting tremor, slowness and rigidity. Disease onset is insidious and progressive, and clinical symptoms are highly variable.

  • Epidemiology and twin studies once refuted a genetic aetiology, but pathogenic mutations were recently described in 7 genes. In the last decade, monogenic parkinsonism has become the most frequent definitive cause of sporadic and familial PD.

  • Symptomatic therapy is currently based on neurotransmitter (dopamine) replacement, but temporal improvement is limited and typically incurs troubling side effects as the disease progresses.

  • Molecular findings continue to nominate targets for rational drug design: primarily pharmacogenomic and neuroprotective therapies.

  • The pathology of PD consists of neuronal loss in the substantia nigra with Lewy body inclusions, whereas many forms of parkinsonism are associated with tauopathy. However, both lesions can represent alternative end points of the same genetic cause.

Abstract

Parkinson disease is a complex, multifactorial neurodegenerative disease. Although a heritable basis was originally thought unlikely, recent studies have implicated several genes in its pathogenesis, and molecular findings now allow accurate diagnosis and challenge past criteria for defining Parkinson disease. Most importantly, genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested. Neuroprotective therapies can now be designed to slow or halt disease progression in affected subjects and asymptomatic carriers.

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Figure 1: The main brain regions affected in Parkinson disease.
Figure 2: SNCA copy number is linked to disease severity, symptoms and age of onset.
Figure 3: Pathways to Parkinson disease.

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Authors and Affiliations

  1. Department of Neuroscience, Morris K. Udall Parkinsons Disease Research Center of Excellence, Birdsall Building, Mayo Clinic, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Matthew James Farrer

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DATABASES

OMIM

Alzheimer disease

diffuse Lewy body disease

Parkinson disease

FURTHER INFORMATION

Familial Parkinson's Disease Laboratory

Glossary

Linkage mapping

A method for localizing genes that is based on the coinheritance of genetic markers and phenotypes in families over several generations.

Association study

A gene-discovery strategy that compares cases with controls to assess the contribution of genetic variants to phenotypes in specific populations. Such studies can test for association with variants in a candidate gene, or with large sets of variants that are located throughout the genome.

Bradykinesia

Slowing of and difficulty in initiating movement that is characteristic of Parkinson disease.

Substantia nigra

The region of the brain that includes the pars compacta and harbours the neurons that produce the neurotransmitter dopamine, which is required for controlled movement. Substantia nigra neurons degenerate in Parkinson disease.

Proteasome

Part of the ubiquitin–proteasome system, in which ubiquitin molecules are attached to a target protein that is subsequently degraded by the proteasome complex.

Relative risk

The ratio of the risk of developing a disease in individuals who have been exposed to a risk factor to that in individuals who have not been exposed to the risk factor.

Longitudinal twin studies

The concordance rate of disease in monozygotic versus dizygotic pairs of twins, which is assessed longitudinally over time.

Cross-sectional twin studies

An assessment of the concordance rate of disease in monozygotic versus dizygotic pairs of twins, carried out at a specific time point.

Penetrance

The frequency with which individuals that carry a given gene will show the manifestations that are associated with the gene. If a disease allele is 100% penetrant then all individuals carrying that allele will express the associated disorder.

Diffuse Lewy body disease

Brain-stem and cortical Lewy body pathology typically associated with clinical dementia and parkinsonism, and with parkinsonism with dementia.

Astrocytosis

The process whereby supporting glial cells in the CNS become activated in response to insult.

Dopaminergic

Refers to neurons that predominantly use dopamine as a neurotransmitter.

Argyrophilic grains disease

A late-onset dementia, with tau-positive 'grains' in neuronal processes and coiled bodies in oligodendrocytes post mortem.

Compound heterozygous

Refers to individuals that carry a diploid genotype in which the two copies of a gene carry different mutations.

Positron emission tomography

Imaging of the emission of positrons from the brain after a small amount of radioactive isotope has been injected into the blood stream. This method is used to quantitatively measure metabolic, biochemical and functional activity in living tissue.

Dyskinesia

Uncontrolled or excessive involuntary movement, which is typically induced as a side-effect of long-term L-DOPA administration.

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Farrer, M. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7, 306–318 (2006). https://doi.org/10.1038/nrg1831

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