Genetic and molecular pathogenesis of Parkinson's disease

Abstract

Parkinson's disease (PD), a common progressive degenerative disease of the central nervous system, affects about 1% of adults aged older than 60 years. PD is characterized by rigidity, tremor, postural instability and bradykinesia, and is attributed to selective degeneration of the nigrostriatal dopaminergic neurons. Recent studies indicate the presence of both genetic and environmental factors in the pathogenesis of PD. While PD is usually sporadic, familial PD cases have been reported, following mostly a Mendelian pattern of inheritance (autosomal dominant or recessive pattern). Six genes have been implicated so far in the pathogenesis of PD (α-synuclein, parkin, UCH-L1, DJ-I, PINK1, and LRRK2), and additional genetic loci are currently under investigation. The proteins encoded by the first three genes are closely related to proteasome function, either as components of the ubiquitin-proteasome system (UPS) function (parkin and UCH-L1) or as degradable substrates (α-synuclein), thereby implicating aberrations in UPS function and protein aggregation as causative events in the pathogenesis of PD. This review describes the genetics and molecular pathogenesis of PD, emphasizing the role of UPS and α-synuclein and commenting on the role of Lewy bodies, the pathological hallmark in sporadic forms and in the majority of inherited forms of PD. Identification of underlying pathogenic mechanisms in PD opens a new era in drug design and intervention.