Autosomal-recessive parkinsonism

Families that inherit PD in a manner compatible with autosomal-recessive disease have long been described, with disease usually manifesting earlier than that in the majority of PD cases. Mutations in the parkin gene were described in
Japanese juvenile-onset cases of disease, and genetic variation in parkin clearly associates with early-onset PD in multiple ethnicities. Apart from the large deletions and rearrangements that inactivate expression, pathogenic point
mutations impart deleterious function compatible with a general loss-of-function disease mechanism. Likewise, loss-of-function mutations that include nonsense
mutations, genomic rearrangements, and missense mutations AU1c have also been described in the PINK1 (PTEN-induced kinase-1) and DJ-1 genes in early-onset cases. In general, overexpression of these proteins usually imparts cytoprotective
properties to cells from a variety of insults. Because most effective drug therapies for a variety of human illnesses involve the ablation or reduction of activity of associated targets, dealing with loss-of-function mechanisms usually imparts additional technical demands on therapeutic strategies. Although the autosomal-recessive genes encode clearly relevant proteins in PD, additional work that characterizes underlying cellular pathways in relevant disease models seems necessary before parkin, PINK1, and DJ-1 can be fully realized as potential therapeutic targets.