LRRK2

Supporting information

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin, is a large multidomain protein kinase that includes leucine-rich repeats and a GTPase domain. LRRK2 is encoded by the PARK8 gene.

Autosomal dominant missense mutations in LRRK2 are commonly associated with late-onset Parkinson's disease (PD); they are also evident in a smaller percentage of familial Parkinson's disease cases, of which they are the most common cause. The discovery of LRRK2 mutations helped strengthen a genetic link to Parkinson's disease, which had previously been obscured by unusual inheritance patterns - in particular, incomplete/decreased penetrance and variable age of onset. Mutations associated with PD have been isolated within the enzymatic domains of LRRK2, namely its kinase and GTPase domains. The most frequent mutation is a substitution of the Gly2019 residue in the kinase domain with a serine residue, resulting in a kinase that exhibits 2- to 3-fold greater catalytic activity. Pathogenic mutations within the Roc (Ras of complex) GTPase domain and COR (carboxy-terminal of Roc) sequence have been shown to decrease GTPase activity, which is thought to counteract LRRK2 activity and restore it to basal levels. Inhibitors of LRRK2 kinase activity have therefore been of therapeutic interest in the treatment of LRRK2-linked PD.

LRRK2 also contains protein-protein interaction domains. Proteins thought to interact with LRRK2 include dishevelled proteins, MAPK kinase 6 (MKK6) and 14.3.3 proteins. Studies have shown that certain members of the 14-3-3 family bind and influence the cytoplasmic localization of LRRK2. PD-associated mutants and a truncated form of LRRK2 show a decreased ability to bind 14-3-3, suggesting that this interaction is important in the pathogenesis of PD.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
Leucine-Rich Repeat Kinase 2 Human LRRK2 XM_058513 Q5S007
Mouse Lrrk2 NM_025730 Q5S006
Rat Lrrk2 NM_001191789 NP_001178718

Literature for LRRK2

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