LRRK2

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling), is an is_associated_with::enzyme that in humans is encoded by the PARK8 is_associated_with::gene. LRRK2 is a member of the is_associated_with::leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of is_associated_with::Parkinson's disease and also is_associated_with::Crohn's disease.

Function
The LRRK2 gene encodes a is_associated_with::protein with an is_associated_with::armadillo repeats (ARM) region, an is_associated_with::ankyrin repeat (ANK) region, a is_associated_with::leucine-rich repeat (LRR) domain, a is_associated_with::kinase domain, a RAS domain, a is_associated_with::GTPase domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane.

LRRK2 interacts with the C-terminal R2 is_associated_with::RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced is_associated_with::apoptotic cell death in neuroblastoma cells and in mouse cortical neurons.

Expression of LRRK2 mutants implicated in autosomal dominant Parkinson's disease causes shortening and simplification of the dendritic tree in vivo and in cultured neurons. This is mediated in part by alterations in macroautophagy,    and can be prevented by protein kinase A regulation of the autophagy protein LC3. The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy. LRRK2 is also a substrate for chaperone-mediated autophagy.

Clinical significance
is_associated_with::Mutations in this gene have been associated with is_associated_with::Parkinson's disease type 8.

The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians. It may also cause sporadic Parkinson's Disease. The mutated Gly amino acid is conserved in all kinase domains of all species.

The Gly2019Ser mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, Gly2019Ser is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry.

Unexpectedly, genomewide association studies have found an association between LRRK2 and is_associated_with::Crohn's disease as well as with Parkinson's disease, suggesting that the two diseases share common pathways.