Human Molecular Genetics, Vol 6, 1687-1691, Copyright © 1997 by Oxford University Press
RL Nussbaum and MH Polymeropoulos
For the past 40 years, research into Parkinson's disease (PD) has been
predominantly the province of epidemiologists interested in pursuing the
connection between the disease and environmental factors such as viral
infection or neurotoxins. Hereditary influences were actually discounted
because of a high monozygotic twin discordance rate found in studies that
were later shown to be inadequate and inconclusive. There has recently been
a resurgence of interest in investigating hereditary factors in PD when it
became more and more apparent that a positive family history was a major
risk factor for the disease. Meanwhile, it also became increasingly
apparent from neuropathological studies that the common, idiopathic form of
Parkinson's disease had, in fact, a pathological correlate, i.e., the
existence of Lewy bodies, an eosinophilic cytoplasmic inclusion body,
distributed diffusely throughout the substantia nigra, hypothalamus,
hippocampus, autonomic ganglia and olfactory tracts. Although candidate
gene approaches to linkage in PD families have not been rewarding, a genome
wide scan mapped PD to 4q21-23 in one large family with PD with diffuse
Lewy bodies, where a candidate gene, alpha-synuclein, resides. This gene
encodes a presynaptic protein of which a peptide fragment is known to be a
constituent of Alzheimer's disease plaques. The identification of a
missense mutation in the alpha-synuclein gene in four independent PD
families suggests that at least some fraction of familial PD with diffuse
Lewy bodies is the result of an abnormal protein that interferes with
normal protein degradation leading to the development of inclusions and
ultimately neuronal cell death. There may be common pathogenetic mechanisms
involved in alpha-synuclein mutations in PD and beta-amyloid and presenilin
gene mutations in Alzheimer's disease.
REVIEWS
Genetics of Parkinson's disease
Laboratory of Genetic Diseases Research, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA. rlnuss@nhgri.nih.gov
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