The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network

Beilina, Alexandra; Bonet-Ponce, Luis; Kumaran, R. Ileng; Kordich, Jennifer J.; Ishida, Morié; Mamais, Adamantios; Kaganovich, Alice; Sáez-Atiénzar, Sara; Gershlick, David C.; Roosen, Dorien A.; Pellegrini, Laura; Malkov, Vladislav A.; Fell, Matthew; Harvey, Kirsten; Bonifacino, Juan S.; Moore, Darren J.; Cookson, Mark

doi:10.1016/j.celrep.2020.107614

Cited by 56 publications

(64 citation statements)

References 70 publications

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“…LRRK2 knockout in rodent models LRRK2 is expressed in many tissues and cell types, with highest expression in lung, kidney, and immune cells and relatively low expression in the brain [88]. LRRK2 knockout mice and rats have discolored kidneys with lysosomal pathology that progresses with age [88][89][90][91][92][93][94]. For example, LRRK2 knockout leads to the formation of large vacuoles, the accumulation of lipofuscin granules, and formation of high-molecular weight ubiquitin-positive protein aggregates in the kidneys [88][89][90][91][92][93].…”

Section: Lrrk2 Deletion Disrupts the Endolysosomal Pathwaymentioning

confidence: 99%

“…The Rab29-LRRK2 pathway is also important for retrograde trafficking as knockout or dominantnegative Rab29 expression disrupts retrograde trafficking of M6PR, Sortilin and Furin from endosomes and lysosomes to the TGN [79,128]. Beilina et al has recently reported a novel interaction between LRRK2, Rab29 and the Golgi-associated retrograde protein (GARP) complex [94]. Specifically, LRRK2 and Rab29 interact with the GARP complex component VPS52 at the TGN.…”

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

“…Specifically, LRRK2 and Rab29 interact with the GARP complex component VPS52 at the TGN. Overexpression of Rab29 recruits VPS52 to the TGN, and this effect is enhanced by co-expression of LRRK2 [94]. Conversely, knockdown of VPS52, or other GARP complex components (VPS53 or VPS51), inhibits Rab29-mediated recruitment of LRRK2 to the TGN, indicating a cooperative stabilization of the Rab29:LRRK2:GARP complex that requires each component [94].…”

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

“…Overexpression of Rab29 recruits VPS52 to the TGN, and this effect is enhanced by co-expression of LRRK2 [94]. Conversely, knockdown of VPS52, or other GARP complex components (VPS53 or VPS51), inhibits Rab29-mediated recruitment of LRRK2 to the TGN, indicating a cooperative stabilization of the Rab29:LRRK2:GARP complex that requires each component [94]. LRRK2 and VPS52 both complex with VAMP4 and syntaxin-6, SNARE proteins that localize to the TGN, suggesting that LRRK2 may stabilize GARP complex interactions with SNARE proteins at the TGN to promote membrane fusion and vesicle trafficking [94].…”

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

“…Conversely, knockdown of VPS52, or other GARP complex components (VPS53 or VPS51), inhibits Rab29-mediated recruitment of LRRK2 to the TGN, indicating a cooperative stabilization of the Rab29:LRRK2:GARP complex that requires each component [94]. LRRK2 and VPS52 both complex with VAMP4 and syntaxin-6, SNARE proteins that localize to the TGN, suggesting that LRRK2 may stabilize GARP complex interactions with SNARE proteins at the TGN to promote membrane fusion and vesicle trafficking [94]. This hypothesis is supported by the observation that LRRK2 or Rab29 knockdown destabilizes the VPS52-syntaxin-6 interaction [94].…”

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

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LRRK2 and the Endolysosomal System in Parkinson’s Disease

Erb

Moore

2020

JPD

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.

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Section: Lrrk2 Deletion Disrupts the Endolysosomal Pathwaymentioning

confidence: 99%

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

Section: Lrrk2 and The Golgi Networkmentioning

confidence: 99%

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LRRK2 and the Endolysosomal System in Parkinson’s Disease

Erb

Moore

2020

JPD

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Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Lai¹,

Alipanahi²,

Fontanillas³

et al. 2021

Annals of Neurology

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ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82–94

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Mendelian Randomization Study Using Dopaminergic Neuron‐Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease

2022

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Background Large‐scale genome‐wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported risk variants confer risk of PD. Objective To nominate genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. Methods We conducted a two‐sample Mendelian randomization (MR) study by integrating large‐scale genome‐wide associations and expression quantitative trait loci (eQTL) data from dopaminergic neurons. Results MR analysis nominated 10 risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. These MR significant genes include FAM200B, NDUFAF2, NUP42, SH3GL2, STX1B, CCDC189, KAT8, PRSS36, VAMP4, and ZSWIM7. Conclusions We report the first MR study of PD by using dopaminergic neuron‐specific eQTL and nominate novel risk genes for PD. Further functional characterization of the nominated risk genes will provide mechanistic insights into PD pathogenesis and potential therapeutic targets. © 2022 International Parkinson and Movement Disorder Society.

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The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network

Cited by 56 publications

References 70 publications

LRRK2 and the Endolysosomal System in Parkinson’s Disease

LRRK2 and the Endolysosomal System in Parkinson’s Disease

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Mendelian Randomization Study Using Dopaminergic Neuron‐Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease

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