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 α-synuclein. LRRK2 mutations are very common in patients with PD, accounting for 40% of patients with sporadic, nonfamilial disease in some ethnic groups. α-synuclein mutations are much less frequent, but the importance of α-synuclein has been confirmed by the demonstration of α-synuclein deposition as Lewy bodies in patients with PD and Lewy body dementia. Pathogenic mutations in α-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 α-synuclein and LRRK2 lead to PD, and how these processes can be therapeutically manipulated, is likely to lead to new disease-modifying treatments.

Keywords::

• α-synuclein
• kinase inhibition
• LRRK2
• neuroprotection
• Parkinson’s disease
• protein aggregation
• therapies
• treatment

Disclosure

Huw Morris has received grant funding from the Parkinson’s disease Society (UK), PSP (Europe) Association and the Ipsen Fund. Huw Morris has sat on advisory boards for Orion and Boerhiger-Ingelheim and has attended educational meetings sponsored by Boerhiger-Ingelheim, Orion, GlaxoSmithKline and Roche.