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LRRK2

MIM.609007 12q12

Sunday 11 June 2006

Definition: Leucine-rich repeat kinase 2 (LRRK2) is a cytosolic kinase.

n 2004, it was first shown that mutations in LRRK2 can cause Parkinson’s disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson’s disease across varied populations.

Further genetic investigation has revealed a variety of genetic ties to Parkinson’s disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression.

A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made.

Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later.

Pathology

- germline mutations in autosomal dominant Parkinson disease

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) were discovered in late-onset parkinsonism, the phenotype of which can be clinically and pathologically indistinguishable from Parkinson disease.

In some kindreds with LRRK2-associated disease, pathologically distinct forms of parkinsonism, including nigral neuronal loss with Lewy body disease or tau-immunopositive neurofibrillary tangles, were discovered.

Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains.

Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. (MIM.607060)

See also

- 8 mutated Parkinson disease genes known (2008)

SNCA PARK2 UCHL1 PINK1 DJ1 LRRK2 ATP13A2 HTRA2

Open References

- LRRK2: cause, risk, and mechanism. Pais├ín-Ruiz C, Lewis PA, Singleton AB. J Parkinsons Dis. 2013;3(2):85-103. doi : 10.3233/JPD-130192 PMID: 23938341 [Free]

References

- Taylor JP, Mata IF, Farrer MJ. LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol Med. 2006 Feb;12(2):76-82. PMID: 16406842

- Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J. The roles of kinases in familial Parkinson’s disease. J Neurosci. 2007 Oct 31;27(44):11865-8. PMID: 17978026