MAPK‐pathway activity, Lrrk2 G2019S, and Parkinson's disease

White, Linda R.; Toft, Mathias; Kvam, Sylvia Nome; Farrer, Matthew J.; Aasly, Jan

doi:10.1002/jnr.21240

Cited by 70 publications

(46 citation statements)

References 25 publications

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“…These studies also suggest that neurite pathology precedes dopaminergic neuronal death by apoptosis (14,15). Although autophagy and increased Tau inclusions have been described in conjunction with neurite shortening, the only signaling pathway linked to the G2019S LRRK2-induced neurite pathology is the ERK pathway (10,15,(17)(18)(19)(20). However, no upstream triggers were identified.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Chan¹,

Citro²,

Cordy³

et al. 2011

Journal of Biological Chemistry

109

111

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are currently the most common genetic cause of familial late-onset Parkinson disease, which is clinically indistinguishable from idiopathic disease. The most common pathological mutation in LRRK2, G2019S LRRK2, is known to cause neurite retraction. However, molecular mechanisms underlying regulation of neurite length by LRRK2 are unknown. Here, we demonstrate a novel interaction between LRRK2 and the Rho GTPase, Rac1, which plays a critical role in actin cytoskeleton remodeling necessary for the maintenance of neurite morphology. LRRK2 binds strongly to endogenous or expressed Rac1, while showing weak binding to Cdc42 and no binding to RhoA. Co-expression with LRRK2 increases Rac1 activity, as shown by increased binding to the p21-activated kinase, which modulates actin cytoskeletal dynamics. LRRK2 constructs carrying mutations that inactivate the kinase or GTPase activities do not activate Rac1. Interestingly, LRRK2 does not increase levels of membrane-bound Rac1 but dramatically changes the cellular localization of Rac1, causing polarization, which is augmented further when LRRK2 is co-expressed with constitutively active Rac1. Four different disease-related mutations in LRRK2 altered binding to Rac1, with the G2019S and R1441C LRRK2 mutations attenuating Rac1 binding and the Y1699C and I2020T LRRK2 mutations increasing binding. Co-expressing Rac1 in SH-SY5Y cells rescues the G2019S mutant phenotype of neurite retraction. We hypothesize that pathological mutations in LRRK2 attenuates activation of Rac1, causing disassembly of actin filaments, leading to neurite retraction. The interactions between LRRK2 and Rho GTPases provide a novel pathway through which LRRK2 might modulate cellular dynamics and contribute to the pathophysiology of Parkinson disease. Parkinson disease (PD)2 is the most common neurodegenerative movement disorder affecting nearly 1% of elderly over 65 years old. Idiopathic PD may result from a combination of factors including age, genetic predisposition, environmental toxins, and neuroinflammation (1, 2). Mutations in LRRK2 are the most common genetic cause of PD and also contribute to many sporadic cases of PD (3, 4). At least 20 mutations identified to date in LRRK2 cause autosomal-dominant PD, accounting for ϳ7% of all familial cases (4, 5). The missense mutation, G2019S, in the kinase domain of LRRK2 is by far the most common of the LRRK2 mutations associated with PD, and disease associated with the G2019S mutations is clinically indistinguishable from idiopathic disease (6).The Lrrk2 gene of 51 exons encodes a large, multidomain protein that includes an ankyrin repeat and leucine-rich repeat regions (6). The kinase domain of LRRK2 shares homology with receptor-interacting protein kinases and mixed lineage kinases (3, 7). LRRK2 also contains a Ras-of-complex (ROC) domain that exhibits GTPase activity (8,9). In between these two domains lies a C-terminal of Ras complex (COR) domain. Each of these domains is thought to be important for bindi...

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Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Chan¹,

Citro²,

Cordy³

et al. 2011

Journal of Biological Chemistry

109

111

View full text Add to dashboard Cite

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“…Two experiments are particularly interesting because they used leukocytes from PD patients with the G2019S mutation (99,100). One study performed protein array analysis to compare MAPK activity between patients and healthy controls and reported that phosphorylation of Src, c-JNK and heat shock protein 27 (HSP27) in patients' samples are lower than in the controls (99).…”

Section: Normal and Pathological Features Of Lrrk2mentioning

confidence: 99%

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

Seol

2010

BMB Reports

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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]

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“…LRRK2 mRNA is highly expressed in the lungs, kidney, spleen and leucocytes; (Biskup et al, 2006;Li et al, 2007;Westerlund et al, 2008;White et al, 2007;Zimprich et al, 2004) however, its expression profile suggests that LRRK2 is unlikely to be an essential developmental protein (Biskup et al, 2007). In adult rodent brain, LRRK2 mRNA is somewhat restricted, with highest levels found in dopamine receptive areas but surprisingly low levels in the dopamine synthesizing areas (Biskup et al, 2006;Galter et al, 2006;Melrose et al, 2006;Simon-Sanchez et al, 2006;Taymans et al, 2006).…”

Section: Lrrk2 Expressionmentioning

confidence: 99%