title: 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.
authors.affiliation: Departments of Pathology, Cell Biology and Neurology, and Taub Institute, Columbia University, New York, NY, 10032, USA.|Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kuwahara
authors.affiliation: Departments of Pathology, Cell Biology and Neurology, and Taub Institute, Columbia University, New York, NY, 10032, USA.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Tetta
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Eguchi
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Shamol
authors.initials: S
authors.lastname: Saha
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Departments of Pathology, Cell Biology and Neurology, and Taub Institute, Columbia University, New York, NY, 10032, USA.
authors.forename: Asa
authors.initials: A
authors.lastname: Abeliovich
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000172:deficiency / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; C000627584:Rab29 protein, mouse; C520110:LRK-1 protein, C elegans; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C505598:Glo-1 protein, C elegans; D020691:rab GTP-Binding Proteins