LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Esteves, A. Raquel; Swerdlow, Russell H.; Cardoso, Sandra M.

doi:10.1016/j.expneurol.2014.05.025

Cited by 88 publications

(77 citation statements)

References 170 publications

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“…[44,45] This is evidenced by the nearly twofold increase in the number of LRRK2 interactors (from 62 to 113) compared to a previous analysis performed in 2014 using an earlier version of the same data processing pipeline. [4] Conversely, the distribution of nodes amongst the other ROCO proteins highlights the comparative neglect of research into characterizing the DAPK1, LRRK1, and MASL1 interactomes.…”

Section: Discussionmentioning

confidence: 99%

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Tomkins

Dihanich²,

Beilina

et al. 2018

Proteomics

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Signal transduction cascades governed by kinases and GTPases are a critical component of the command and control of cellular processes, with the precise outcome partly determined by direct protein–protein interactions (PPIs). Here, we use the human ROCO proteins as a model for investigating PPI signaling events—taking advantage of the unique dual kinase/GTPase activities and scaffolding properties of these multidomain proteins. PPI networks are reported that encompass the human ROCO proteins, developed using two complementary approaches. First, using the recently developed weighted PPI network analysis (WPPINA) pipeline, a confidence-weighted overview of validated ROCO protein interactors is obtained from peer-reviewed literature. Second, novel ROCO PPIs are assessed experimentally via protein microarray screens. The networks derived from these orthologous approaches are compared to identify common elements within the ROCO protein interactome; functional enrichment analysis of this common core of the network identified stress response and cell projection organization as shared functions within this protein family. Despite the presence of these commonalities, the results suggest that many unique interactors and therefore some specialized cellular roles have evolved for different members of the ROCO proteins. Overall, this multi-approach strategy to increase the resolution of protein interaction networks represents a prototype for the utility of PPI data integration in understanding signaling biology.

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Section: Discussionmentioning

confidence: 99%

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Tomkins

Dihanich²,

Beilina

et al. 2018

Proteomics

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“…LRRK2 is a complex kinase consisting of LRR, ROC, COR, kinase, and WD40 domains [37]. Accumulated evidence suggests that LRRK2 plays a key role in axonal extension, autophagy, proliferation, and survival of neurons [38, 39]. In addition to neurons, LRRK2 is highly expressed in immune cells such as B cells, macrophages, and microglia [40–43].…”

Section: Introductionmentioning

confidence: 99%

Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia

et al. 2016

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Backgroundα-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson’s disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated. In this study, we investigated αSYN clearance by microglia isolated from LRRK2-knockout (KO) mice.ResultsIn LRRK2-KO microglia, αSYN was taken up in larger amounts and cleared from the supernatant more effectively than for microglia isolated from wild-type (WT) mice. This higher clearance ability of LRRK2-KO microglia was thought to be due to an increase of Rab5-positive endosomes, but not Rab7- or Rab11-positive endosomes. Increased engagement between Rab5 and dynamin 1 was also observed in LRRK2-KO microglia.ConclusionLRRK2 negatively regulates the clearance of αSYN accompanied by down-regulation of the endocytosis pathway. Our findings reveal a new functional role of LRRK2 in microglia and offer a new insight into the mechanism of PD pathogenesis.

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“…LRRK2 protein levels are thought to be effectively regulated by miR-205 through a conserved binding site, while patients with sporadic PD demonstrated signifi cantly reduced levels of miR-205, resulting in elevated LRRK2 levels and neurite outgrowth [ 116 ]. The role of LRRK2 in disease pathogenesis is still unclear, although its function as a kinase and GTPase implicates this protein in a number of molecular pathways possibly implicated with PD [ 117 ]. Nevertheless, in a drosophila model mutated LRRK2 was found to interact with microRNA biogenesis through an RNA -independent association with the RISC complex [ 118 ].…”

Section: Mirnas and Neurodegenerationmentioning

confidence: 98%

MicroRNAs in Disease

Papagregoriou

2015

Genomic Elements in Health, Disease and Evolution

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LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Cited by 88 publications

References 170 publications

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia

MicroRNAs in Disease

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