In a new study, published in Neuron, researchers have found that variants of leucine-rich repeat kinase 2 (LRRK2) and RAB7L1 interact genetically and functionally to enhance the risk of sporadic Parkinson disease (PD). The findings highlight the protein-sorting pathway as a therapeutic target in PD.

Knockdown of RAB7L1 in rat neurons reduces localization of lysosomes (red) with the Golgi apparatus (blue). Image courtesy of A. Abeliovich.

Studies of familial PD have provided evidence of genetic and functional associations between risk genes, but whether such interactions occur in the more-common sporadic form was unclear. “We used a brain transcriptomic approach as a starting point, and focused initially on unaffected carriers of PD risk variants,” explains Asa Abeliovich, lead researcher of the study. “The working hypothesis was that although carriers of the risk alleles generally don't develop PD, these variants could still affect aspects of brain pathology.”

Variants at two PD-associated risk loci, LRRK2 and PARK16, had similar and overlapping effects on the brain. “We showed that the effect of these variants on PD risk are not independent, suggesting a common mechanistic pathway,” explains Abeliovich. Notably, the PARK16 locus encompasses five possible PD risk genes, but only overexpression of one, RAB7L1, could suppress LRRK2 mutation-induced shortening of neurites in vitro.

The PD-linked PARK16 haplotype is associated with alternative splicing of RAB7L1 that leads to exclusion of a key activation domain of the gene. In vitro studies revealed that truncated RAB7L1 could not rescue the mutant-LRRK2 phenotype of neurites. Furthermore, a significant reduction in full-length RAB7L1 was found in the brains of patients with PD.

Knockdown of LRRK2 or RAB7L1 in rat neurons caused lysosomal swelling, indicating that these genes are linked to the retromer pathway, which is involved in intraneuronal trafficking of proteins. Overexpression of wild-type, but not mutant, VPS35—a retromer component in which rare mutations have recently been linked to familial PD—suppressed the mutant LRRK2 or RAB7L1 phenotype in rodent neurons in vitro and Drosophila dopaminergic neurons in vivo.

“These data suggest that improving retromer pathway function in PD would be therapeutic, so we are pursuing this direction,” says Abeliovich.