Data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss-of-function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations.
results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer-dimer dynamics and thereby trap its GTPase domain in an activated state.
The vast majority of familial LRRK2-dependent PD cases are heterozygous; thus these findings raise the possibility that a crucial factor in disease pathogenesis may be the accumulation of homo-dimeric mutant LRRK2.
The data imply that Rab32 is linked to SNX6/retromer trafficking at the Golgi and also suggests a possible connection between the retromer and Rab32 in the trafficking and biological functions of LRRK2.
This defect was restored by LRRK2-IN-1 treatment in LRRK2 patients only. Our results suggest that PD forms due to LRRK2 and PARK2 mutations involve pathogenic mechanisms converging on PINK1/Parkin-dependent mitophagy.
LRRK2 Roc-COR forms guanine nucleotide-dependent -like homodimers it exhibits conventional Ras-like GTPase properties with high-affinity binding of Mg(2+) -GTP/GDP and low intrinsic catalytic activity.
Studied leucine rich repeat kinase 2 (LRRK2)-WAS protein family member 2 (WAVE2) pathway in modulation of phagocytosis in leukocytes as well as its possible role for altered immune function in Parkinson's Disease.
this study has mapped for the first time the domain within LRRK2 that mediates the interaction with FADD thereby activating the molecular machinery of the extrinsic death pathway.
Results suggest reciprocal regulation between LRRK2 and Rab protein substrates where Rab7L1-mediated upregulation of LRRK2 kinase activity results in the stabilization of membrane and GTP-bound Rab proteins that may be unable to interact with Rab effector proteins.
These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.
Authors find that human G2019S-LRRK2 markedly enhances the neuron-to-neuron transmission of tau in transgenic mice. Data suggest that mutant tau-induced neuropathology occurs independently of LRRK2 expression but identifies a novel pathogenic role for G2019S-LRRK2 in promoting the neuronal transmission of WT-tau protein.
LRRK2-induced apoptosis was suppressed by ASK1 inhibition in neuronal stem cells derived from patients with Parkinson's disease (PD). These results clearly indicate that LRRK2 acts as an upstream kinase in the ASK1 pathway and plays an important role in the pathogenesis of PD
Study showed that LRRK2 phosphorylation is required for LRRK2 to bind to Fbxl18 and that this interaction is important for regulating the amount of LRRK2 via ubiquitination of LRRK2 by the SCFFbxl18 ubiquitin ligase and subsequent proteasomal degradation of LRRK2. We also show that LRRK2 can induce caspase 8 mediated cell death and that the degradation of LRRK2 mediated by Fbxl18 can prevent LRRK2-mediated toxicity.
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