Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed. [BMB reports 2010; 43(4): 233-244]

Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3

“…Several lines of evidence implicate that altered kinase activity of LRRK2 may play an important role in neurodegeneration (34,35). In addition, LRRK2 is a phosphoprotein, being phosphorylated at various sites via either autophosphorylation or upstream kinases (7,18).…”

RIP kinases: key decision makers in cell death and innate immunity

“…Similarly, the functions of RIP6 and RIP7 (also known as leucine-rich repeat kinases 1 and 2) are unknown although both have been associated with the pathogenesis of Parkinson's disease. 13,14 Although our understanding of the biology of RIP4-7 is still in its infancy, intensive research has clarified important molecular and physiological roles of RIP1-3 in inflammation and cell death, the core focus of the remainder of this review.…”

Leucine-Rich Repeat Kinase 2 Modulates Neuroinflammation and Neurotoxicity in Models of Human Immunodeficiency Virus 1-Associated Neurocognitive Disorders

“…LRRK2 is a large, multidomain protein that is expressed in immune cells, microglia, and neurons (Melrose et al, 2006;Seol, 2010). Mutations in LRRK2 account for the most common genetic cause of PD and primarily result in increased kinase activity (Zimprich et al, 2004;West et al, 2007;Gloeckner et al, 2010).…”