RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk

MacLeod, David; Rhinn, Hervé; Kuwahara, Tomohiro; Zolin, Ari; Paolo, Gilbert Di; McCabe, Brian D.; Marder, Karen; Honig, Lawrence S.; Clark, Lorraine N.; Small, Scott A.; Abeliovich, Asa

doi:10.1016/j.neuron.2012.11.033

Cited by 499 publications

(537 citation statements)

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“…130 and Beilina et al . 118 showed a genetic interaction between LRRK2 and Rab7L1; a genetic risk factor for sporadic PD.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 91%

“…118 showed a genetic interaction between LRRK2 and Rab7L1; a genetic risk factor for sporadic PD. Expression of G2019S ‐LRRK2 in primary neurons induced lysosomal swelling and accumulation of a component of the retromer complex; the mannose phosphate receptor 130. The mannose phosphate receptor is normally recycled between endolysosomes and the Golgi apparatus 131.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 99%

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Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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“…130 and Beilina et al . 118 showed a genetic interaction between LRRK2 and Rab7L1; a genetic risk factor for sporadic PD.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 91%

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…If viable, this therapeutic approach would not only turn out to be beneficial for AD, but perhaps also be useful for other disorders where endosomal dysfunction has been described, for example PD [23]. Several studies have recently implicated the retromer complex itself in PD [24][25][26]. To date, a dozen genes have been implicated in PD, including a point mutation (D620N) in Vps35, which results in autosomal dominant familial PD [27,28].…”

Section: Retromer In Other Diseasesmentioning

confidence: 99%

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

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“…Immunofluorescence analyses on GFP-Rab29-expressing cells showed that Rab29 colocalizes with GM130 (cis-Golgi) and TGN46 (trans-Golgi network), similar to epithelial cells. 15,18,19 Rab29 also colocalized with Rab11, while a limited colocalization was observed with both Rab4 (recycling endosomes) and Rab5 (early endosomes) (Figures 1c-e). Based on our findings implicating IFT20 in TCR recycling 5,14 as well as on the association of TCRζ with Rab8 11 which is similar to IFT20 is implicated in ciliogenesis, 21 the colocalization of Rab29 with these proteins was assessed.…”

mentioning

confidence: 92%

“…15,16 Rab32 and Rab38 participate in the generation and traffic of melanosomes, 17 while Rab29 regulates retrograde endolysosome-to-Golgi trafficking of the mannose-6-phosphate receptor (MPR) in epithelial and neuronal cells. 18,19 Based on the implication of Rab29 in typhoid toxin trafficking to the plasma membrane from the SCV, 15 where Rab4 and Rab11 have also been observed, 20 here we assessed the role of Rab29 in the regulation of TCR recycling. The results identify Rab29 as a novel regulator of vesicular trafficking in T cells, acting as a complex with IFT20 and the Rabs Rab8 and Rab11 to control TCR recycling and IS assembly.…”

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confidence: 99%

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

et al. 2015

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Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11 + endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly. T-cell activation is triggered by T-cell antigen receptor (TCR) engagement by MHC-bound peptide dispayed by an antigen presenting cell (APC). While a substantial proportion of the TCR has long been known to be associated with recycling endosomes, 1 it is only recently that the central function of this pool has emerged with the finding that, on assembly of the specialized interface with the APC, known as the immune synapse (IS), intracellular TCRs are delivered to this location by polarized recycling. 2 This process ensures a steady supply of TCRs at the IS to sustain signaling for T-cell activation 3 and has been co-opted by other receptors, such as the transferrin receptor (TfR) and the chemokine receptor CXCR4, 4,5 as well as membrane-bound signaling mediators, such as the kinase Lck and the adaptor LAT. 6,7 Receptor recycling is orchestrated by the small GTPases Rab4 and Rab11. 8 Cargo specificity is achieved with the assistance of specific regulators and effectors. The TCR recycling pathway has only started to be delineated with the identification of specific mediators, which include Rab35 and its GAP EPI64C 9 and the actin adaptor WASH 10 . Specific combinations of Rabs and SNAREs have been recently associated with recycling endosomes carrying either Lck, or TCRζ and LAT. 11 We have moreover identified IFT20 12 and other components of the intraflagellar transport (IFT) system, which regulates ciliary assembly and function, 13 as unexpected regulators of TCR recycling in the non-ciliated T cell. 14 Recently a Rab GTPase subfamily, which includes Rab29, Rab32 and Rab38, has been implicated in trafficking of the Salmonella-containing vacuole (SCV) in infected epithelial cells. 15,16 Rab32 and Rab38 ...

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RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk

Cited by 499 publications

References 48 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

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