LRRK2 mediates tubulation and vesicle sorting from lysosomes

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Genetic variations in LRRK2 are linked to Parkinson's disease (PD) risk.
• The precise biological roles of LRRK2 are not fully understood.
• Lysosomes play a critical role in PD pathogenesis.

Purpose of the Study:

• To elucidate the functions of LRRK2 in cellular processes.
• To identify LRRK2 interacting partners at the lysosome.
• To characterize a novel LRRK2-mediated cellular mechanism.

Main Methods:

• Cellular exposure to lysosome membrane-disrupting agents.
• Unbiased proteomic screening to identify protein interactions.
• Super-resolution live-cell imaging and FIB-SEM microscopy.
• Kinase assays and phosphosite analysis.

Main Results:

• LRRK2 is recruited to lysosomes upon cellular stress.
• JIP4 is identified as a lysosomal LRRK2-binding partner.
• LRRK2, via RAB35/RAB10 phosphorylation, recruits JIP4 to lysosomes.
• JIP4 promotes the formation of LAMP1-negative tubules for lysosomal content release.
• A novel LRRK2-orchestrated pathway, LYTL, is described.

Conclusions:

• LRRK2 regulates a new cellular pathway, LYTL, involving lysosomal tubulation and content release.
• The LYTL pathway, mediated by LRRK2 and JIP4, is potentially relevant to Parkinson's disease.
• Understanding LYTL may provide new therapeutic targets for PD.