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

• DOI: 10.1038/srep29945
• Publication Date: 2016-07-18T09:21:15Z
• Authors: Tomoki Kuwahara; Keiichi Inoue; Vivette D. D’Agati; Tetta Fujimoto; Tomoya Eguchi; Shamol Saha; Benjamin Wolozin; Takeshi Iwatsubo; Asa Abeliovich
• Keywords: Motor Neurons; 0301 basic medicine; 610; Membrane Proteins; Endosomes; Protein Serine-Threonine Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Article; Axons; Cell Line; Kidney Tubules, Proximal; Mice; Protein Transport; 03 medical and health sciences; HEK293 Cells; rab GTP-Binding Proteins; Nervous system--Diseases; Pathology; Animals; Humans; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Lysosomes; Protein Binding

AbstractLeucine-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.