Genetics of Parkinson disease: paradigm shifts and future prospects

• Published in: Nature reviews. Genetics Vol. 7; no. 4; pp. 306 - 318
• Main Author: Farrer, Matthew James
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2006; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine; Environment; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genes, Dominant; Genes, Recessive; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Human Genetics; Humans; Medical sciences; Mutation; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Parkinson Disease - classification; Parkinson Disease - genetics; Parkinson Disease - therapy; Parkinson's disease; Proteins; review-article; Signal Transduction; Twin studies; Twins; United States > US; Nervous system diseases; Central nervous system disease; Parkinson disease; Degenerative disease; Cerebral disorder; Extrapyramidal syndrome; Genetic disease
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg1831

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. Genetic studies of Parkinson disease have stimulated progress in understanding many aspects of this debilitating neurodegenerative disorder. A combination of mapping disease genes in humans and studying their functions in model organisms provides new hope for treatment and prevention. 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.