Autosomal dominant Parkinson's disease and the route to new therapies

Abstract

The pathogenesis of Parkinson's disease (PD) is not understood and there are currently no accepted disease modifying, neuroprotective treatments. There are two autosomal dominant PD genes, leucine-rich repeat kinase (LRRK)2 and alpha-synuclein. LRRK2 mutations are very common in patients with PD, accounting for 40% of patients with sporadic, nonfamilial disease in some ethnic groups. Alpha-synuclein mutations are much less frequent, but the importance of alpha-synuclein has been confirmed by the demonstration of alpha-synuclein deposition as Lewy bodies in patients with PD and Lewy body dementia. Pathogenic mutations in alpha-synuclein accelerate the formation of oligomers and fibrils. Mutations in LRRK2 lead to an enhancement in LRRK2 kinase activity. The further study and understanding of the route by which alpha-synuclein and LRRK2 lead to PD, and how these processes can be therapeutically manipulated, is likely to lead to new disease-modifying treatments.