The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading cause of familial Parkinson's disease (PD).
• The precise mechanisms governing LRRK2's localization, function, and degradation remain incompletely understood.

Purpose of the Study:

• To identify novel interactors of LRRK2 and elucidate the regulatory pathways controlling its cellular behavior.
• To investigate the role of tripartite motif family 1 (TRIM1) in modulating LRRK2 function and its implications in Parkinson's disease.

Main Methods:

• Quantitative mass spectrometry-based interactome studies to identify LRRK2-binding proteins.
• Biochemical assays to characterize the interaction between TRIM1 and LRRK2, including specific binding domains.
• Analysis of LRRK2 phosphorylation status and its effect on protein interactions.
• Cellular assays to assess the impact of TRIM1 on LRRK2 localization, degradation, kinase activity, and neurite outgrowth.

Main Results:

• Identified 48 novel LRRK2 interactors, including the E3 ubiquitin ligase TRIM1.
• TRIM1 binds LRRK2 at the 'regulatory loop' (amino acids 911-919) and recruits it to microtubules for ubiquitination and proteasomal degradation.
• LRRK2 phosphorylation at Ser910/Ser935 influences its binding to 14-3-3 versus TRIM1.
• TRIM1 binding modulates LRRK2-Rab29 interaction and inhibits Rab29-mediated LRRK2 kinase activation.
• TRIM1 expression rescues neurite outgrowth defects induced by the PD-associated LRRK2 G2019S mutation.

Conclusions:

• TRIM1 is a key regulator of LRRK2, controlling its degradation, subcellular localization, and interaction partners.
• TRIM1 modulates LRRK2 kinase activity in an E3 ligase-dependent manner.
• TRIM1 acts as a protective factor against LRRK2-mediated neurotoxicity relevant to Parkinson's disease pathogenesis.