Leucine-rich repeat kinases

LKRK2 Leucine-rich repeat kinase dardarin 12ql2 Dominant Unknown... 

PD is generally a sporadic disorder, but in a significant proportion of cases (10-15% in most studies) it runs in families without a clearcut Mendelian pattern. Currently, there have been 13 defined loci identified as associated with high-penetrant autosomal dominant or recessive PD, of which causative mutations in specific genes have been identified. These genes include a-synuclein, parkin, ubiquitin carboxyl-terminal esterase LI (UCH-Ll), PTEN-induced putative kinase 1 (PlNKl), DJ-1, and leucine-rich repeat kinase 2 (LRRK2). As outlined in Table 3, most of these mutations can be characterized by an early onset of disease. 

Higashi S, Moore DJ, Colebrooke RE, Biskup S, Dawson VL, Arai H, Dawson TM, Emson PC (2007b) Expression and localization of Parkinson s disease-associated leucine-rich repeat kinase 2 in the mouse brain. J Neurochem 100 368-381 Higgins GA, Jacobsen H (2003) Transgenic mouse models of Alzheimer s disease phenotype and application. Behav Pharmacol 14 419—438... 

Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 102 18676-18681... 

West AB, Moore DJ, Biskup S, Bugayenko A, Smidi WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson s disease-associated mutadons in leucine-rich repeat kinase 2 augment kinase acd vity. Proc Nad Acad Sci USA 102 16842-16847. 

Keywords Dopamine Glial-derived neurotrophic factor Lewy body Leucine-rich repeat kinase 2 MPTP Nigrostriatal pathway Paraquat Parkin Rotenone Alpha-Synuclein... 

Leucine Rich Repeat Kinase 2 (LRRK2) mutations lead to late-onset PD, in an autosomal dominant pattern, with variable age-at-onset. To date, the S2019G mutation is by far the most common (>50%) and appears to have arisen at chfferent times in the past. However, the biological function of LRRK2 is currently not known. 

West, A.B., Moore, D.J., Biskup, S., et al. Parkinson s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102, 16842-16847 (2005). doi 10.1073/pnas.0507360102... 

Ness, D., Ren, Z., Gardai, S., Sharpnack, D., Johnson, V. J., Brennan, R. J., Brigham, E. R, and Olaharski, A. J. (2013). Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal mbule injury and perturbations in metabolic and immunological homeostasis. PLoS One 8, e66164. 

Garofalo and coworkers reported the discovery and preparation of a novel series of cinnoline-3-carboxamides as inhibitors of leucine-rich repeat kinase 2 (LRRK2) activity and proposed their potential application as therapeutics for treating Parkinson s disease (Figure 2) (13BMCL71). While these cinnoline-3-carboxamides exhibited good potencies and were found to penetrate the central nervous system (CNS), they lacked specificity. The most potent compounds were determined to be... 

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