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

Neuron. 2013 Feb 6;77(3):425-39. doi: 10.1016/j.neuron.2012.11.033.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Animals, Genetically Modified
  • Animals, Newborn
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / pathology*
  • Drosophila
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Green Fluorescent Proteins / genetics
  • Humans
  • Immunoprecipitation
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Male
  • Mice
  • Middle Aged
  • Mutation / genetics
  • Neurons / metabolism*
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / pathology
  • Polymorphism, Single Nucleotide / genetics
  • Protein Transport / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Statistics as Topic
  • Synaptosomal-Associated Protein 25 / genetics
  • Synaptosomal-Associated Protein 25 / metabolism
  • Transfection
  • Tubulin / genetics
  • Tubulin / metabolism
  • Tyrosine 3-Monooxygenase
  • Vesicle-Associated Membrane Protein 2 / genetics
  • Vesicle-Associated Membrane Protein 2 / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Synaptosomal-Associated Protein 25
  • Tubulin
  • Vesicle-Associated Membrane Protein 2
  • Green Fluorescent Proteins
  • rab7 protein
  • Tyrosine 3-Monooxygenase
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins

Supplementary concepts

  • Parkinson Disease 16