Abstract
Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson’s disease (PD), Crohn’s disease, and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models.
Highlights
Human genetic studies of Parkinson’s disease (PD) patient cohorts have previously suggested that common variants at LRRK2 function coordinately with variants at a second PD risk-associated locus, PARK16, to increase PD risk, as human genetic variants at these 2 loci impact PD risk non-additively[10,11]
LRK-1 functions within a genetic pathway consisting of GLO-1 as well the adaptor protein complex 3 (AP-3) component, APB-3, which is essential for vesicular endosomal trafficking to lysosomes or lysosome-related organelles (LROs)[26,27]
We analyzed nematodes that harbor either of two independent lrk-1 mutant alleles: km[17], a deletion lacking the C-terminal portion of the gene that includes the kinase domain, or tm1898, a frameshift mutation within the leucine-rich repeat region that is predicted to result in a truncated protein lacking all known functional domains (Fig. 1A). lrk-1 mutants exhibited a significantly increased frequency of ALM axon overextension: ALM neurons typically extend a single axon anteriorly which terminates caudal to the tip of the nose, lrk-1 mutants occasionally harbored ALM axons that extended all the way to the tip of the nose and folded back, resulting in a hook-like structure (Fig. 1B)
Summary
Human genetic studies of PD patient cohorts have previously suggested that common variants at LRRK2 function coordinately with variants at a second PD risk-associated locus, PARK16, to increase PD risk, as human genetic variants at these 2 loci impact PD risk non-additively[10,11]. Pneumocytes25 – two cell types that are known to have active lysosomal transport compartments, further supporting a broad role for LRRK2 in lysosomal function Such animals have been reported to display only limited and inconsistent brain pathology. LRK-1 functions within a genetic pathway consisting of GLO-1 as well the adaptor protein complex 3 (AP-3) component, APB-3, which is essential for vesicular endosomal trafficking to lysosomes or lysosome-related organelles (LROs)[26,27]. Double mutant mice displayed a non-additive phenotype, consistent with a common mechanism of action Taken together, these results implicate a physiological RAB7L1-LRRK2 pathway in the regulation of AP-3-dependent functions, such as intracellular trafficking of lysosome-bound proteins and the regulation of axonal morphology, in diverse cellular and organismal contexts
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