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Genetics of Parkinson's disease
R L Nussbaum1, M H Polymeropoulos
1Laboratory of Genetic Diseases Research, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA. rlnuss@nhgri.nih.gov
Human Molecular Genetics
|January 1, 1997
Summary
Genetic factors are increasingly recognized in Parkinson's disease (PD), a neurodegenerative disorder. Mutations in the alpha-synuclein gene are linked to familial PD with Lewy bodies, suggesting shared pathways with Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Parkinson's disease (PD) research historically focused on environmental factors, largely discounting genetic influences due to inconclusive early studies.
- A positive family history is now recognized as a significant risk factor for PD.
- Neuropathological studies identified Lewy bodies as a hallmark of idiopathic PD.
Purpose of the Study:
- To investigate the role of hereditary factors in Parkinson's disease.
- To identify genetic mutations associated with familial PD and Lewy body formation.
Main Methods:
- Genome-wide scan to map PD loci in affected families.
- Candidate gene analysis focusing on alpha-synuclein, located in a mapped PD region.
- Genetic sequencing to identify mutations in the alpha-synuclein gene.
Main Results:
- A genome-wide scan identified a locus for PD with diffuse Lewy bodies at 4q21-23.
- The alpha-synuclein gene, encoding a presynaptic protein, resides within this locus.
- Missense mutations in the alpha-synuclein gene were found in four independent PD families.
Conclusions:
- Familial Parkinson's disease with diffuse Lewy bodies can result from alpha-synuclein gene mutations.
- Abnormal alpha-synuclein protein may disrupt normal protein degradation, leading to Lewy body formation and neuronal death.
- Common pathogenetic mechanisms may link alpha-synuclein mutations in PD with genetic factors in Alzheimer's disease.