New Gene for Familial Parkinson’s Disease Located
New Gene for Familial Parkinson’s Disease Located
Abstract & Commentary
Source: Bonifati V, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256-259.
Ten loci and genes have been linked to familial Parkinson’s disease, and their chromosomal location and mode of inheritance are listed in Table 1. Mutations in a-synuclein and parkin have been described in families with Parkinson’s disease, and both gene products are involved in the function of the proteosome, a major pathway for degradation of proteins within the cell. In the current report, Bonifati and colleagues report their isolation of the DJ-1 gene in 2 consanguineous, genetically isolated families in The Netherlands and Italy.
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Table 1. |
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The Genetics of Familial Parkinson’s Disease |
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| Locus | Chromosome | Gene | Inheritance |
| PARK1 | 4q21.3 | a-synuclein | AD |
| PARK2 | 6q25 | parkin | AR |
| PARk3 | 2p13 | ? | AD |
| PARK4 | 4p15 | ? | AD |
| PARK5 | 4p14 | UCH-L1(?) | AD |
| PARK6 | 1p35 | ? | AR |
| PARK7 | 1p36 | DJ-1 | AR |
| PARK8 | 12p11 | ? | AD |
| PARK9 | 1p36 | ? | AR |
| PARK10 | 1p32 | ? | ? |
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Adapted from Dawson and Dawson. J Clin Investigation. 2003;111: 145-151. |
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Mutations in the DJ-1 locus are responsible for PARK7 parkinsonism. DJ-1 mutations completely cosegregated with clinical phenotype in these 2 families. The DJ-1 gene contains 8 exons and encodes a 189-amino-acid protein that is widely expressed throughout the body and the brain. It is closely related to known bacterial proteases. Based on structural models of the protein, the mutation in the Italian family likely enhances the ability of the protein to aggregate as multimers. The function of DJ-1 in man is unknown. However, it is responsive to hydroperoxide and may function in the cell as an antioxidant. The possibility exists that DJ-1 functions in dopamine neurons to buffer reactive oxygen species produced by normal metabolism of dopamine.
Bonifati et al also explored the function of DJ-1 by transfecting cells in cell culture with the gene. Wild-type DJ-1-transfected cells showed that the protein is normally diffusely expressed throughout the nucleus and cytoplasm. In contrast, cells transfected with mutant DJ-1 showed cytoplasmic concentration of the protein almost completely within mitochondria.
Commentary
This report documents the third major locus for genetic forms of Parkinson’s disease. To date, all identified genes are involved in the proteosome system or in cascades that modulate oxidative stress within the cell. Progress in the field of Parkinson genetics parallels strides made a decade ago in Alzheimer’s disease. In that disease, different genetic mutations in proteins involved in processing of the amyloid precursor protein produced highly similar clinical and pathological phenotypes. The current discovery of the DJ-1 gene is an important step in understanding the molecular mechanisms of nigral cell degeneration in inherited and sporadic Parkinson’s disease. — Steven Frucht
Dr. Frucht is Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center.
CorrectionCME question No. 6 in the March 2003 issue had 2 correct answers. This question will be eliminated.
Mutations in a-synuclein and parkin have been described in families with Parkinsons disease, and both gene products are involved in the function of the proteosome, a major pathway for degradation of proteins within the cell.Subscribe Now for Access
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