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

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Cytoplasmic aggregation of transactive response DNA-binding protein-43 (TDP-43) is a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.
• The role of protein disulfide isomerase (PDI), a chaperone enzyme, in TDP-43 pathology remains unclear.

Purpose of the Study:

• To investigate the interaction between PDI and TDP-43.
• To determine PDI's effect on TDP-43 aggregation and its pathological consequences.

Main Methods:

• Investigated the interaction between wild-type PDI and TDP-43.
• Assessed PDI's impact on TDP-43 phase separation and condensate formation.
• Examined PDI's role in TDP-43 mislocalization, phosphorylation, and aggregation in cellular models.

Main Results:

• Wild-type PDI attenuates TDP-43 phase separation and disassembles TDP-43/G3BP1 condensates.
• PDI counteracts TDP-43 mislocalization, abnormal phosphorylation, and aggregation, alleviating mitochondrial damage and neuronal toxicity.
• Abnormal PDI loses its activity, leading to TDP-43 amyloid fibril formation, mitochondrial impairment, and neuronal cell death in ALS and AD-TDP models.

Conclusions:

• PDI plays a critical role in preventing TDP-43 aggregation and subsequent neurotoxicity.
• Dysfunctional PDI contributes to the pathogenesis of TDP-43 proteinopathies.
• PDI emerges as a potential therapeutic target for neurodegenerative diseases characterized by TDP-43 pathology.