RGD Reference Report - RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. - Rat Genome Database

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RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.

Authors: MacLeod, DA  Rhinn, H  Kuwahara, T  Zolin, A  Di Paolo, G  McCabe, BD  Marder, KS  Honig, LS  Clark, LN  Small, SA  Abeliovich, A 
Citation: MacLeod DA, etal., Neuron. 2013 Feb 6;77(3):425-39. doi: 10.1016/j.neuron.2012.11.033.
RGD ID: 8553873
Pubmed: PMID:23395371   (View Abstract at PubMed)
PMCID: PMC3646583   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuron.2012.11.033   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of retrograde transport, endosome to Golgi involved_inIMPUniProtKB:Q96QK18553873PMID:23395371ParkinsonsUK-UCL 
retrograde transport, endosome to Golgi involved_inIMP 8553873PMID:23395371ParkinsonsUK-UCL 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Golgi apparatus located_inIDA 8553873PMID:23395371ParkinsonsUK-UCL 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q5S0078553873PMID:23395371IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Rab29  (RAB29, member RAS oncogene family)
Vps35  (VPS35 retromer complex component)


Additional Information