LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses

Area of Science:

• Cell Biology
• Neuroscience
• Biochemistry

Background:

• Increased leucine-rich repeat kinase 2 (LRRK2) activity is a significant risk factor for Parkinson's disease.
• LRRK2's localization to lysosomal membranes suggests lysosome physiology regulates its activation.
• The precise mechanisms linking lysosomal perturbations to LRRK2 activation remain largely unknown.

Purpose of the Study:

• To elucidate how leucine-rich repeat kinase 2 (LRRK2) integrates upstream signals from lysosomal challenges.
• To investigate the roles of Rab GTPases and GABARAP in mediating LRRK2 activation in response to distinct lysosomal perturbations.
• To establish a mechanistic framework for LRRK2 regulation in both physiological and pathological contexts of Parkinson's disease.

Main Methods:

• Analysis of cellular responses to osmotic challenges and membrane integrity disruptions.
• Investigating LRRK2 activation through manipulations affecting lysosome enlargement (e.g., PIKfyve inhibition).
• Examining LRRK2 activation under conditions of lysosome deacidification and CASM-dependent GABARAP lipidation.

Main Results:

• LRRK2 integrates multiple upstream cues via parallel interactions with Rab GTPases and GABARAP.
• Osmotic swelling induces Rab accumulation on lysosomes, leading to Rab-dependent LRRK2 activation independently of GABARAP.
• Lysosome deacidification triggers CASM-dependent GABARAP lipidation, creating a platform that cooperates with Rabs for LRRK2 activation.

Conclusions:

• LRRK2 activation is modulated by distinct lysosomal perturbations through complementary Rab- and GABARAP-dependent pathways.
• These findings provide a mechanistic understanding of how LRRK2 senses and responds to changes in lysosome function.
• This work offers a framework for understanding LRRK2 regulation in Parkinson's disease pathogenesis.