March 2013

MacLeod and colleagues report the discovery of a sporadic Parkinson’s disease (PD) risk gene, RAB7L1, and its interaction with two genes linked to familial PD (LARRK2 and VSP35) in a common functional pathway. They began with an unbiased screen, comparing transcriptome-wide gene expression profiles of autopsy brain tissue from unaffected individuals who share a risk or protective allele at 7 PD-associated risk loci. Expression profiles for the risk variants were most similar to transcriptome changes found in brain tissue from persons affected with PD, but not other CNS disorders. Among the 7 loci, profiles for the PARK16 locus and LRRK2 were most alike and analysis of 4 independent GWAS indicated genetic interaction between these loci. Among the five candidate genes in the PARK 16 locus only RAB7L1 interacted with LRRK2 in regulating neurite outgrowth from rat cortical neurons and in maintaining dopamine neuron survival in Drosophila. Analysis of existing human splicing data demonstrated an association of the PARK16 haplotype with exon 2 skipping in RAB7L1, and studies with a minigene containing risk and protective variants at the common SNP within the PARK16 locus demonstrated increased skipping with the risk allele. Studies of protein sorting revealed a functional interaction between LRRK2 and RAB7L1. Expression of LRRK2 G2019S, which causes autosomal dominant PD, led to lysosomal swelling and reduced accumulation of the mannose-6-phosphate receptor (MPR) in lysosomes; these phenotypes were mimicked by RAB7L1 knockdown and suppressed by RAB7L1 overexpression. MPR is recycled between endolysosomes and the Golgi by a group of proteins that form the retromer complex, including VPS35, and mutations in the VPS35 gene have been recently linked to rare familial forms of PD. Overexpression of VPS35 suppressed lysosomal and neurite outgrowth deficits caused by LRRK2 G2019S expression or RAB7L1 knockdown. Moreover, expression of LRRK2 disease mutants or RAB7L1 knockdown led to reduced levels of VPS35 and another retromer protein, VPS29 in cultured cells and mouse brain. Taken together these results indicate the existence of a LRRK2-RAB7L1 pathway that regulates retromer function at the Golgi and that enhancing retromer function may be of therapeutic value in PD (Neuron 2013;77:425–439).