Recent advances in research on Parkinson disease: synuclein and parkin.
BACKGROUND
Until recently, most research effort on Parkinson disease (PD) was focused on possible environmental causes. With the discovery of mutations in two genes, synuclein and parkin, which are responsible for rare familial forms of the disease, there has been a major change in emphasis.


RESULTS
The first genetic cause of PD to be identified was in the gene for synuclein, resulting in an alanine to threonine substitution at position 53. The likely pathogenetic significance of this mutation was supported by the discovery of a second mutation, and the presence of synuclein in Lewy bodies in sporadic PD cases. The synuclein protein has a tendency to self aggregate, and this tendency is increased in the mutants, and by oxidative injury to the protein. While there is growing evidence in animal models that overexpression of wildtype or mutant synuclein may lead to intracytoplasmic inclusions, and dysfunction of dopamine neurons, no animal models in rodents have yet replicated all important features of the disease. Deletions or point mutations in the gene for parkin cause an autosomal recessive, early onset form of parkinsonism. The parkin protein functions as an E3 ubiquitin-protein ligase, and it is involved in the degradation of cellular proteins by the proteasomal pathway. It is hypothesized that the loss of this function results in the toxic accumulation of its target proteins.


CONCLUSIONS
Research on these inherited forms of PD is pointing towards a common theme, that disturbances of cellular protein handling can lead to the death of dopamine neurons in PD.
Burke
Robert E
RE
Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. rb43@columbia.edu
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex; D013572:Synaptic Vesicles / Q000378:metabolism; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex