Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no cure.
• Genetic factors are increasingly implicated in ALS, but their impact on motor neuron degeneration and shared cellular pathways is unclear.

Purpose of the Study:

• To identify binding partners of wild-type and mutant ALS-associated proteins using interactomic analysis.
• To understand how genetic mutations in ALS proteins affect cellular pathways and protein interactions.
• To investigate the role of shared interactors, like FMRP, in ALS pathogenesis.

Main Methods:

• Performed interactomic analysis on neuronal cells for wild-type and mutant ATXN2, C9orf72, FUS, OPTN, TDP-43, and UBQLN2.
• Analyzed shared binding partners and their cellular functions.
• Investigated the role of fragile X mental retardation protein (FMRP) in in vitro and in vivo models of FUS-ALS.

Main Results:

• Identified numerous known and novel binding partners for ALS proteins.
• Mutations in OPTN and UBQLN2 altered protein interactions, while others showed conserved interactomes.
• Shared interactors implicated RNA metabolism (ATXN2, FUS, TDP-43), protein degradation/transport (OPTN, UBQLN2), and mitochondrial function (C9orf72).
• FMRP localized to mutant FUS aggregates and directly bound FUS.
• FMRP expression rescued FUS-mutation-induced defects in zebrafish models.

Conclusions:

• Interactomics provides critical insights into ALS disease mechanisms.
• Identified shared pathways affected by ALS-linked genetic mutations.
• Demonstrated a link between FMRP and motor neuron dysfunction in FUS-ALS, suggesting FMRP as a potential therapeutic target.