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

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

doi:10.1016/j.neuron.2013.02.021

Cited by 83 publications

(168 citation statements)

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“…This SNP is located 8.5 kb upstream of RAB7L1 , which encodes the RAB7L1 protein that is involved in vesicle trafficking and in maintaining the integrity of the trans‐Golgi network [Beilina et al, ]. LRRK2 , an established PD gene, has been shown to interact with this protein [MacLeod et al, ].…”

Section: Discussionmentioning

confidence: 99%

PARK16 is associated with PD in the Malaysian population

Gopalai

Ahmad‐Annuar

et al. 2016

American J of Med Genetics Pt B

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PARK16 was identified as a risk factor for Parkinson's disease in a Japanese cohort; however, subsequent studies in the other populations including the Chinese, European, Caucasian, and Chilean have shown a protective role instead. To investigate this locus in our Malaysian cohort, 1,144 individuals were screened for five SNPs in the PARK16 locus and logistic regression analysis showed that the A allele of the rs947211 SNP reduced the risk of developing PD via a recessive model (Odds ratio 0.57, P-value 0.0003). Pooled analysis with other Asian studies showed that A allele of the rs947211 SNP decreased the risk of developing PD via a recessive model (Odds ratio 0.71, P-value 0.0001). In addition, when meta-analysis was performed with other Asian population, three SNPs (rs823128, rs823156, and rs11240572) reduced risk of developing PD via a dominant model. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

PARK16 is associated with PD in the Malaysian population

Gopalai

Ahmad‐Annuar

et al. 2016

American J of Med Genetics Pt B

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“…A second RAB GTPase shown to be associated with LRRK2 is RAB7L1/RAB29 . RAB7L1 maps to Parkinson Disease 16 (PARK16), a locus of 5 genes that is a genetic risk factor for idiopathic PD .…”

Section: Functional Linkages Between Rab Gtpases and Lrrk2mentioning

confidence: 99%

“…RAB7L1 maps to Parkinson Disease 16 (PARK16), a locus of 5 genes that is a genetic risk factor for idiopathic PD . MacLeod and colleagues showed that overexpression of either WT or constitutively active RAB7L1 orthologue in a drosophila model rescued dopamine neuron loss and premature mortality induced by LRRK2 p.Gly2019Ser. In addition, the overexpression of WT or constitutively active RAB7L1 in rat primary neuronal cells overexpressing LRRK2 p.Gly2019Ser rescued phenotypes such as lysosomal swelling and reduced neurite process length during outgrowth .…”

Section: Functional Linkages Between Rab Gtpases and Lrrk2mentioning

confidence: 99%

“…MacLeod and colleagues showed that overexpression of either WT or constitutively active RAB7L1 orthologue in a drosophila model rescued dopamine neuron loss and premature mortality induced by LRRK2 p.Gly2019Ser. In addition, the overexpression of WT or constitutively active RAB7L1 in rat primary neuronal cells overexpressing LRRK2 p.Gly2019Ser rescued phenotypes such as lysosomal swelling and reduced neurite process length during outgrowth . In contrast, the overexpression of WT Rab7L1 in WT primary mouse cortical cultures caused neurite shortening, perhaps as a result of the dysregulation of the stoichiometric ratio of components of the LRRK2 complex that are required for normal LRRK2 function .…”

Section: Functional Linkages Between Rab Gtpases and Lrrk2mentioning

confidence: 99%

“…The function of the retromer complex in the endo‐lysosomal pathway overlaps with that of LRRK2 and RAB7L1. In cell models with reduced RAB7L1 activity, or cell and animal models overexpressing PD‐associated mutant forms of LRRK2, there is a significant decrease in the steady‐state levels of VPS26, VPS29, and VPS35 . This implies that a deficiency in retromer activity may contribute to the neuropathology underlying LRRK2‐mediated PD and requires further investigation.…”

Section: Interactions Between Rab Gtpase and Vps35mentioning

confidence: 99%

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The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease

et al. 2018

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The identification of pathogenic mutations in Ras analog in brain 39B (RAB39B) and Ras analog in brain 32 (RAB32) that cause Parkinson's disease (PD) has highlighted the emerging role of protein trafficking in disease pathogenesis. Ras analog in brain (Rab) Guanosine triphosphatase (GTPase) function as master regulators of membrane trafficking, including vesicle formation, movement along cytoskeletal networks, and membrane fusion. Recent studies have linked Rab GTPases with α-synuclein, Leucine-rich repeat kinase 2, and Vacuolar protein sorting 35, 3 key proteins in PD pathogenesis. In this review, we discuss the various RAB GTPases associated with PD, current progress in the research, and potential future directions. Investigations into the function of RAB GTPases will likely provide significant insight into the etiology of PD and identify novel therapeutic targets for a currently incurable disease. © 2018 International Parkinson and Movement Disorder Society.

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The functional roles of retromer in Parkinson's disease

2017

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The endosomal system is critical for the maintenance of intracellular homeostasis, and defects in this system are often linked to neurological disorders. The retromer complex is a critical coordinator of endosomal dynamics and has functional roles in multiple cellular processes through sorting cargoes from endosomes to the trans-Golgi network (TGN) or to the plasma membrane. Mammalian retromer comprises a core Vps26-Vps35-Vps29 trimer and associates with a range of proteins to generate endosomal tubular-vesicular carriers. Alterations in retromer function or its molecular organization have been a rising risk factor for Parkinson's disease (PD). Although genetic evidence has shown several variants within retromer in late-onset PD cases, the exact molecular machineries by which retromer variants induce the development of PD are still not completely elucidated. In this Review, we will focus on the functional roles of retromer in neuronal health, summarize advances in defining the cellular pathological phenotype caused by retromer deficiency or PD-linked retromer variants and discuss the potential clues of how retromer deregulation may contribute to PD pathogenesis.Keywords: autophagy; endosomal trafficking; lysosome; mitochondria; Parkinson's disease (PD); retromer The endosomal network is a highly dynamic and orchestrated system, which serves a vital function in coordinating the communication and exchange of associated proteins and lipids between intracellular membrane-bounded compartments. Once within the network, cargo molecules originating from the plasma membrane and biosynthetic pathways are targeted to a common sorting station, the early endosome, from where cargoes are sorted towards specialized intracellular locations following multiple trafficking routes. They can be either sorted into late endosomes/ lysosomes for degradation or retrieved to the plasma membrane or the trans-Golgi network (TGN). The efficient and accurate delivery of cargo contents within intracellular compartments is critical for the maintenance of intracellular homeostasis, and defects on it are often associated with multiple human diseases. The evolutionary conserved protein complex, termed Abbreviations AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; APEX, ascorbate peroxidase; APP, b-amyloid precursor protein; ATG9A, autophagy-associated protein; Ab, elevated b-amyloid peptide; BAR, Bin-Amphiphysin-Rvs; BDNF, brain-derived neurotrophic factor; CI-M6PR, cation-independent mannose 6-phosphate receptor; CLN5, ceroid lipouscinosis neuronal protein-5; CMA, chaperon-mediated autophagy; Crb, crumb; DA, dopaminergic; DMTI-II, divalent metal transporter II; DRD1, dopamine receptor D1; Drp1, dynamin-related protein 1; EHD1, Eps15 homology domain-containing protein-1; FERM, 4.1/ezrin/radixin/moesin; GLUT1, glucose transporter 1; Kir3, G protein-gated inward rectifying potassium channels; Lamp2a, lysosome-associated membrane glycoprotein 2a; LBs, Lewy bodies; MAPL, mitochondria-anchored protein ligase; MDVs, mitochondria-de...

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

Cited by 83 publications

References 0 publications

PARK16 is associated with PD in the Malaysian population

PARK16 is associated with PD in the Malaysian population

The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease

The functional roles of retromer in Parkinson's disease

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