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

Sci Rep. 2016 Jul 18;6:29945. doi: 10.1038/srep29945.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / ultrastructure
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line
  • Endosomes / metabolism
  • Endosomes / ultrastructure
  • HEK293 Cells
  • Humans
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / deficiency
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Membrane Proteins / metabolism
  • Mice
  • Motor Neurons / metabolism
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Membrane Proteins
  • Rab29 protein, mouse
  • LRK-1 protein, C elegans
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Glo-1 protein, C elegans
  • rab GTP-Binding Proteins