LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts

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.

Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase

“…Genetic investigations in Caenorhabditis elegans neurons revealed that the RAB29 (GLO‐1) orthologue acts upstream of LRRK2 (LRK‐1) in a signaling pathway controlling axon termination (Kuwahara et al , ). It was also reported that Rab29 and LRRK2 double‐knockout mice exhibit an enlarged kidney phenotype that was non‐additive, relative to single Rab29 or LRRK2 knockout, further implying that these genes act in a common pathway (Kuwahara et al , ).…”

Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

“…These association studies suggest that LRRK2 and Rab GTPases may interact in the pathogenesis of PD. Interestingly, Rab7L1 -deficient mice share similar kidney phenotypes and lysosomal defects as LRRK2 −/− mice, providing further support for a functional connection between LRRK2 and Rab proteins (Kuwahara et al, 2016). Future studies will be needed to elucidate how LRRK2 interacts with RAB7L1 and other Rab proteins in the regulation of the autophagy-lysosomal pathways.…”

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

“…Further supporting the idea that LRRK2 and Rabs co-operate to modulate vesicular trafficking, Rab7L1 KO mice have the same lysosomal pathology in the kidneys as LRRK2 KO mice and the combined deficiency of both proteins also results in a similar phenotype suggesting a genetic interaction with consistent direction between these two proteins [78]. Whether this is true for other Rabs that are direct substrates of LRRK2 is not known, and future studies are required to further substantiate the relationship between LRRK2, Rabs and regulation of the autophagy-lysosome system.…”

“…Furthermore, cellular work showed that LRRK2 interacts with AP-3 as a downstream effector, essential for trafficking of lysosomal membrane proteins from the Golgi to the lysosomes [78]. The Drosophila homolog of LRRK2 (dLrrk) colocalizes with endosomes and lysosomes and interacts late endosomal protein Rab7.…”