Leucine-rich repeat kinase-2
The gene LRRK2 at 12q12 codes for the 2527 amino acid leucine-rich repeat kinase-2, mutations of which have been associated with familial Parkinsons disease. Leucine-rich repeat serine/threonine-protein kinase 2 up regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway and appears to be key to regulation of internal protein trafficking in cells.
PARK8 OMIM:607060 is an autosominal dominant form of familial Parkinson's disease caused by mutations in LRRK2. Mean age of onset is 65 years, and there is a good response to levodopa. Families are in Japan, England, the Basque region of Spain and Nebraska. Other variations of the gene are found in idiopathic Parkinson's disease, Lewy body dementia (OMIM:127750) or various forms of frontotemporal dementia (OMIM:600274).
Small molecule inhibitors of leucine-rich repeat kinase-2 are under development such as MLi-2 in an attempt to stimulate normal autophagy in Parkinsons disease.