Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.

Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.