Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the mislocalization and aggregation of TAR DNA binding protein 43 (TDP-43).
• TDP-43 aggregation in the cytoplasm is a key pathological hallmark, driving disease progression.
• Directly reducing TDP-43 is not a viable therapeutic approach due to its essential cellular functions.

Purpose of the Study:

• To identify and characterize genes that modify TDP-43 mislocalization and aggregation.
• To explore the therapeutic potential of targeting these modifier genes in ALS.

Main Methods:

• Utilized inducible mutant TDP-43 HEK293 cell lines and primary rat neurons.
• Employed knockdown of RAD23A and USP13 genes.
• Applied discovery-based proteomics to analyze proteome remodeling.
• Assessed TDP-43 solubility, aggregation, and cytotoxicity in cellular and C. elegans models.

Main Results:

• Knockdown of RAD23A reduced insoluble TDP-43 levels in cellular and neuronal models.
• Proteomic analysis identified USP13 (a deubiquitinase) as a modifier of TDP-43 aggregation.
• Knockdown of USP13 decreased TDP-43 aggregation, reduced cell death in motor neurons, and improved motor function in C. elegans.

Conclusions:

• RAD23A and USP13, components of the ubiquitin proteasome system, are significant modifiers of TDP-43 pathology.
• Targeting RAD23A and USP13 enhances TDP-43 solubility and reduces TDP-43-induced neurotoxicity.
• These findings suggest that targeting modifier genes like RAD23A and USP13 represents a promising therapeutic avenue for ALS.