Autosomal dominant Parkinson's disease and the route to new therapies.Expert Rev Neurother 2007; 7(6):649-56ER
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.