Common genetic variants at the PARK16 locus and within the LRRK2 gene modify an individual's risk of getting Parkinson's disease. Now, David MacLeod et al. demonstrate how variations at these loci interact to affect lysosomal function and neuronal health (Neuron 77, 425–439).

The PARK16 locus is composed of five separate genes. The researchers found that expression of only one of these genes, RAB7L1, can restore neurite outgrowth in cultured rat neurons that express mutant LRRK2. RAB7L1 expression could also reduce lysosomal swelling caused by mutant LRRK2. When the authors expressed LRRK2 and RAB7L1 in cell lines, they observed that the proteins could bind each other and that both localized within the same intracellular compartments.

The researchers showed that the PARK16 variant that increased Parkinson's disease risk led to alternative splicing of RAB7L1 and truncation of RAB7L1 protein. This version of RAB7L1 could not restore neurite outgrowth in cultured rat neurons expressing mutant LRRK2.

MacLeod et al. showed that expressing mutant LRRK2 or reducing the expression of RAB7L1 in a cell line led to loss of components of the retromer complex, which regulates protein sorting from the lysosome. Interestingly, overexpression of VPS35, a retromer component that had previously been linked to familial Parkinson's disease, could restore neurite outgrowth in rat neurons expressing mutant LRRK2. Although the mechanism by which LRRK2 and RAB7L1 affect retromer expression remains to be determined, these findings demonstrate a functional relationship between three loci that affect Parkinson's disease risk, which all impinge on cellular protein sorting.