Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation

Tomoki Kuwahara, Kai Funakawa, Tadayuki Komori, Maria Sakurai, Gen Yoshii, Tomoya Eguchi, Mitsunori Fukuda, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Leucine-rich repeat kinase 2 (LRRK2), the major causative gene product of autosomal-dominant Parkinson's disease, is a protein kinase that phosphorylates a subset of Rab GTPases. Since pathogenic LRRK2 mutations increase its ability to phosphorylate Rab GTPases, elucidating the mechanisms of how Rab phosphorylation is regulated by LRRK2 is of great importance. We have previously reported that chloroquine-induced lysosomal stress facilitates LRRK2 phosphorylation of Rab10 to maintain lysosomal homeostasis. Here we reveal that Rab10 phosphorylation by LRRK2 is potently stimulated by treatment of cells with a set of lysosome stressors and clinically used lysosomotropic drugs. These agents commonly promoted the formation of LRRK2-coated enlarged lysosomes and extracellular release of lysosomal enzyme cathepsin B, the latter being dependent on LRRK2 kinase activity. In contrast to the increase in Rab10 phosphorylation, treatment with lysosomotropic drugs did not increase the enzymatic activity of LRRK2, as monitored by its autophosphorylation at Ser1292 residue, but rather enhanced the molecular proximity between LRRK2 and its substrate Rab GTPases on the cytosolic surface of lysosomes. Lysosomotropic drug-induced upregulation of Rab10 phosphorylation was likely a downstream event of Rab29 (Rab7L1)-mediated enzymatic activation of LRRK2. These results suggest a regulated process of Rab10 phosphorylation by LRRK2 that is associated with lysosomal overload stress, and provide insights into the novel strategies to halt the aberrant upregulation of LRRK2 kinase activity.

Original languageEnglish
Article number105081
JournalNeurobiology of Disease
Volume145
DOIs
Publication statusPublished - 2020 Nov

Keywords

  • LRRK2
  • Lysosome
  • Lysosomotropic agents
  • Parkinson's disease
  • Phosphorylation
  • Rab

ASJC Scopus subject areas

  • Neurology

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