[Animal models for familial Parkinson's disease].

Parkinson's disease (PD) is the second most common neurodegenerative disorder among elderly people. 5-10% of PD cases are familial and presumably hereditary forms. Based on the genes responsible for familial PD, genetic PD animal models were produced and provided invaluable information as to the pathogenetic mechanisms of PD. Missense mutations or gene multiplications of alpha-synuclein lead to autosomal dominant form of familial PD termed PARK1 or PARK4, respectively. Transgenic (Tg) mice expressing mutant of wild-type alpha-synuclein replicated main clinical features of PD including Lewy body-like aggregate formation. Inactivation of Parkin E3 enzyme leads to autosomal recessive form of PD without Lewy body formation. We have identified Pael-R as a substrate of Parkin. Accumulation of Pael-R induced by Parkin deletion evokes endoplasmic reticulum (ER) stress, resulting in cell death in cultured cells, Pael-R Tg Drosophila and Parkin-knockout crossed with Pael-R Tg mice. Recently Parkin-deficient and PTEN-induced kinase 1 (PINK1)-deficient flies showed almost identical phenotype: muscle and sperm degeneration accompanied by mitochondrial abnormalities. PINK1 is the gene for PARK6, an autosomal recessive PD. Interestingly, overexpression of Parkin rescued the phenotype of PINK1-deleted fly and Parkin/PINK1 double knockout Drosophila did not aggravated the phenotype of either Parkin or PINK1 single knockouts, indicating that Parkin and PINK1 are located in the common signaling pathway, in which Parkin works downstream of PINK1. Further studies on familial PD animal models will elucidate the roles and relationships of ubiquitin-proteasome system, endoplasmic reticulum and mitochondria in the pathogenesis of PD.