title: RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
abstract: Recent genome-wide association studies have linked common variants in the human genome to Parkinson's disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 ortholog in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.
authors: Department of Neurology and Taub Institute, Columbia University, Black Building 1208, 650 West 168th Street, New York, NY 10032, USA.
authors: David A
authors: DA
authors: MacLeod
authors: Herve
authors: H
authors: Rhinn
authors: Tomoki
authors: T
authors: Kuwahara
authors: Ari
authors: A
authors: Zolin
authors: Gilbert
authors: G
authors: Di Paolo
authors: Brian D
authors: BD
authors: McCabe
authors: Brian D
authors: BD
authors: MacCabe
authors: Karen S
authors: KS
authors: Marder
authors: Lawrence S
authors: LS
authors: Honig
authors: Lorraine N
authors: LN
authors: Clark
authors: Scott A
authors: SA
authors: Small
authors: Asa
authors: A
authors: Abeliovich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology*; D004330:Drosophila; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D050825:Synaptosomal-Associated Protein 25; D014404:Tubulin; D050988:Vesicle-Associated Membrane Protein 2; D000090802:rab7 GTP-Binding Proteins; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins
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