PubMed_ArguminSci  

PubMed:21454543 JSONTXT 32 Projects

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Id Subject Object Predicate Lexical cue
T1 95-293 DRI_Background denotes 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.
T2 294-341 DRI_Background denotes The most common pathological mutation in LRRK2,
T3 354-393 DRI_Background denotes , is known to cause neurite retraction.
T4 394-485 DRI_Background denotes However, molecular mechanisms underlying regulation of neurite length by LRRK2 are unknown.
T5 486-680 DRI_Outcome denotes 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.
T6 681-794 DRI_Outcome denotes LRRK2 binds strongly to endogenous or expressed Rac1, while showing weak binding to Cdc42 and no binding to RhoA.
T7 795-948 DRI_Outcome denotes Co-expression with LRRK2 increases Rac1 activity, as shown by increased binding to the p21-activated kinase, which modulates actin cytoskeletal dynamics.
T8 949-1054 DRI_Approach denotes LRRK2 constructs carrying mutations that inactivate the kinase or GTPase activities do not activate Rac1.
T9 1055-1292 DRI_Outcome denotes 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.
T10 1293-1387 DRI_Approach denotes Four different disease-related mutations in LRRK2 altered binding to Rac1, with the G2019S and
T11 1401-1454 DRI_Approach denotes mutations attenuating Rac1 binding and the Y1699C and
T12 1468-1497 DRI_Approach denotes mutations increasing binding.
T13 1498-1592 DRI_Background denotes Co-expressing Rac1 in SH-SY5Y cells rescues the G2019S mutant phenotype of neurite retraction.
T14 1593-1746 DRI_Outcome denotes We hypothesize that pathological mutations in LRRK2 attenuates activation of Rac1, causing disassembly of actin filaments, leading to neurite retraction.
T15 1747-1930 DRI_Challenge denotes 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.