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

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, and its pathogenesis has not been fully elucidated. TAR DNA-binding protein 43 (TDP-43), as one of the key pathogenic genes in ALS, participates in the disease process through interactions with various proteins. This study aims to investigate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in ALS. Methods: HEK293T cell models transfected with wild-type and mutant TDP-43 (TDP-43 M337V ) plasmids were constructed. The interaction between TDP-43 and ALDOA was analyzed through proteomic screening of specific peptides and co-immunoprecipitation, and the co-localization of the two in cells was detected by immunofluorescence. Changes in ALDOA expression levels after intervention with mutant TDP-43 were detected by Western blot and quantitative real-time PCR. Results: Proteomic analysis identified ALDOA as a potential interacting protein of TDP-43. Protein-protein interaction (PPI) analysis, co-immunoprecipitation, and immunofluorescence experiments further confirmed that both wild-type and mutant TDP-43 interact with ALDOA. Western blot and quantitative real-time PCR results showed that, compared with the wild-type TDP-43 group, the ALDOA expression was significantly increased in the TDP-43 M337V mutant group. Conclusion: TDP-43 interacts with ALDOA in ALS, and the TDP-43 M337V mutation significantly promotes ALDOA expression, suggesting that ALDOA may be involved in the pathogenesis of TDP-43-mediated ALS. These findings provide new insights into the pathogenesis of ALS and highlight a potential therapeutic target.