LRRK2 deficiency impairs trans-Golgi to lysosome trafficking and endocytic cargo degradation in human renal proximal tubule epithelial cells

Am J Physiol Renal Physiol. 2018 Nov 1;315(5):F1465-F1477. doi: 10.1152/ajprenal.00009.2018. Epub 2018 Aug 8.


Defects in vesicular trafficking underlie a wide variety of human diseases. Genetic disruption of leucine-rich repeat kinase 2 (LRRK2) in rodents results in epithelial vesicular trafficking errors that can also be induced by treatment of animals with LRRK2 kinase inhibitors. Here we demonstrate that defects in human renal cells lacking LRRK2 phenocopy those seen in the kidneys of Lrrk2 knockout mice, characterized by accumulation of intracellular waste vesicles and fragmentation of the Golgi apparatus. This phenotype can be recapitulated by knockdown of N-ethylmaleimide-sensitive factor, which physically associates with LRRK2 in renal cells. Deficiency in either protein leads to a defect in trans-Golgi to lysosome protein trafficking, which compromises the capacity of lysosomes to degrade endocytic and autophagic cargo. In contrast, neither bulk endocytosis nor autophagic flux are impaired when LRRK2 is acutely knocked down in normal immortalized human kidney (HK2) cells. These data collectively suggest that the primary renal defect caused by LRRK2 deficiency is in protein trafficking between the Golgi apparatus and late endosome/lysosome, which leads to progressive impairments in lysosomal function.

Keywords: Golgi apparatus; LRRK2; NSF; lysosome; vesicle trafficking.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autophagy
  • Cell Line
  • Cell Proliferation
  • Endocytosis*
  • Epithelial Cells / enzymology*
  • Epithelial Cells / pathology
  • Gene Knockdown Techniques
  • Genotype
  • Golgi Apparatus / enzymology*
  • Golgi Apparatus / pathology
  • Humans
  • Kidney Tubules, Proximal / enzymology*
  • Kidney Tubules, Proximal / pathology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / deficiency*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Lysosomes / enzymology*
  • Lysosomes / pathology
  • N-Ethylmaleimide-Sensitive Proteins / genetics
  • N-Ethylmaleimide-Sensitive Proteins / metabolism
  • Phenotype
  • Protein Transport
  • Proteolysis


  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • N-Ethylmaleimide-Sensitive Proteins
  • NSF protein, human