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Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling), is is a large, multi-domain kinase that in humans is encoded by the PARK8 gene. LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of familial Parkinson's disease as well as Crohn's disease and leprosy. The function of the kinase is poorly understood, but research points to involvement in the autophagy pathway, as well as structural involvement in neuron development.

Discovery
The gene coding for LRRK2, PARK8, located on chromosome 12, was discovered in 2002 by a study of a Japanese family showing a dominant inheritance pattern for Parkinson's disease. This discovery made a large impact on the study of Parkinson's disease, which previously had been thought to be caused almost exclusively by environmental toxins. The protein for which this gene codes was subsequently isolated by a separate group studying a family from the Basque region of France. The name for this protein, "dardarin", which the group coined from the Basque word for tremor, was later replaced by the more descriptive name, Leucine-Rich Repeat Kinase 2.

Structure and Function
LRRK2 is a large, 286 kDa enzyme that dimerizes under cellular conditions.

Similarities between portions of LRRK2's amino acid sequence and domains studied in other proteins provide clues about the structure and function of LRRK2. The location of pathological mutations highlights the domains which are essential to the normal function of the enzyme.

Mutations
Several common mutations that contribute to an increased probability of developing Parkinson's disease have been identified in the LRRK2 enzyme. The most common mutations fall in the kinase domain. The most frequent mutation is a substitution of glycine for serine at the 2019th amino acid residue, commonly identified as the G2019S mutation. This mutation has consistently shown an increase the kinase activity of LRRK2, in both in vitro autophosphorylation and phosphorylation of synthetic peptide substrates.

Clinical Significance
Mutations in the PARK8 gene have been associated with familial Parkinson's disease, Crohn's disease, and leprosy.

Familial Parkinson’s disease
The G2019S mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians. It is also a common mutation found in idiopathic, or non-familial cases of Parkinson's disease. Around 11% of familial Parkinson’s disease cases have this mutation, but the frequency may be higher or lower in different ethnic populations.

Clinically, familial Parkinson’s disease is indistinguishable from sporadic Parkinson’s disease. There is a complete overlap of the physical and behavioral symptoms between sporadic and familial Parkinson’s disease, other than the inheritance patterns. Interestingly, a small percentage of sporadic Parkinson’s disease cases have been shown to have the G2019S mutation, despite no family history of Parkinson’s disease.

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.

Other diseases
Unexpectedly, genomewide association studies have found an association between LRRK2 and Crohn's disease as well as with Parkinson's disease, suggesting that the two diseases share common pathways. LRRK2 has also been implicated in an increased susceptibility to infections by Mycobacterium leprae and Mycobacterium lepromatosis, known commonly as leprosy. Although Parkinson's Disease, inflammatory bowl disease, and a bacterial infection seem unrelated, the autophagy and apoptosis pathways play an integral role in the development of these diseases, which indicates LRRK2’s involvement in these pathways.

Tissue expression and cellular localization
Although LRRK2 mutations have been shown to affect the nervous system, as in familial Parkinson’s disease, expression of LRRK2 may be higher in other tissue types, such as the liver, heart, and kidneys. Expression of the pathogenic protein in areas of the body other than the brain, however, is not an uncommon pattern for neurodegenerative diseases.

Cellular localization studies have shown that LRRK2 is located mainly in the cytosol, although several studies have shown that LRRK2 may localize to the outer membrane of mitochondria.