40 - Genetics of parkinsonism

Summary

Overview

Over the last few years, several genes for monogenically inherited forms of Parkinson's disease have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy body pathology, mutations have been identified in the gene for α-synuclein. Aggregation of this protein in Lewy bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy body formation. Parkin mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. This potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. The most recently identified PD-genes are DJ-1 and PINK1, again in families with autosomal-recessive inheritance and early onset. Other loci have been mapped to chromosome 2p and 12p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes.