Mechanisms of lysosomal tubulation and sorting driven by LRRK2

Biochem Soc Trans. 2024 Aug 28;52(4):1909-1919. doi: 10.1042/BST20240087.

Abstract

Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. Lysosomal dysfunction plays a central role in the pathobiology of Parkinson's disease (PD). Gain-of-function mutations in Leucine-rich repeat kinase 2 (LRRK2) cause familial PD and genetic variations in its locus increase the risk of developing the sporadic form of the disease. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by LRRK2), wherein membrane-damaged lysosomes generate tubules sorted into mobile vesicles. Subsequently, these vesicles interact with healthy lysosomes. LYTL is orchestrated by LRRK2 kinase activity, via the recruitment and phosphorylation of a subset of RAB GTPases. Here, we summarize the current understanding of LYTL and its regulation, as well as the unknown aspects of this process.

Keywords: Parkinson's disease; RAB proteins; leucine-rich repeat kinase.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / metabolism
  • Lysosomes* / metabolism
  • Mutation
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / pathology
  • Phosphorylation
  • Protein Transport
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • rab GTP-Binding Proteins
  • LRRK2 protein, human