Proteomic Identification of ALDOA as a Pathogenic TDP-43 Interaction Partner in ALS

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease impacting motor neurons.
• The precise pathogenesis of ALS remains incompletely understood.
• TAR DNA-binding protein 43 (TDP-43) is a key protein implicated in ALS pathogenesis through its interactions.

Purpose of the Study:

• To elucidate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in the context of ALS.
• To investigate the role of TDP-43 and ALDOA in ALS pathogenesis.

Main Methods:

• Utilized HEK293T cell models expressing wild-type and mutant TDP-43 (TDP-43^M337V).
• Employed proteomic screening, co-immunoprecipitation, and immunofluorescence to analyze TDP-43 and ALDOA interactions and co-localization.
• Assessed ALDOA expression levels via Western blot and quantitative real-time PCR following TDP-43 mutation intervention.

Main Results:

• Proteomic analysis identified ALDOA as a potential TDP-43 interacting protein.
• Co-immunoprecipitation and immunofluorescence confirmed interactions between both wild-type and mutant TDP-43 with ALDOA.
• Significantly elevated ALDOA expression was observed in cells with TDP-43^M337V mutation compared to wild-type TDP-43.

Conclusions:

• TDP-43 directly interacts with ALDOA in ALS models.
• The TDP-43^M337V mutation demonstrably increases ALDOA expression.
• ALDOA is implicated in the pathogenesis of TDP-43-mediated ALS, presenting a potential therapeutic target.