Protein Disulfide Isomerase Disassembles TDP‐43/G3BP1 Condensates and Antagonizes TDP‐43 Pathological Aggregates
Source abstract
Abstract
ABSTRACT 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.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Amyotrophic Lateral Sclerosis Research · Endoplasmic Reticulum Stress and Disease · Nerve injury and regeneration
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Hubei Key Laboratory of Cell Homeostasis College of Life Sciences Wuhan University Wuhan China
Key Laboratory of Radiopharmaceuticals Ministry of Education College of Chemistry Beijing Normal University Beijing China
Department of Neurology Peking University Third Hospital Beijing China
Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases the First Affiliated Hospital Dalian Medical University Dalian China
Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica Hubei Engineering Research Center for Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and Technology Wuhan China
Institute of Neurology, Sichuan Academy of Medical Sciences‐Sichuan Provincial Hospital Medical School of University of Electronic Science and Technology of China Chengdu China
Center For Advanced Materials Research & Faculty of Arts and Sciences Beijing Normal University At Zhuhai Zhuhai China
Funding
National Natural Science Foundation of China · National Key Research and Development Program of China · National Major Science and Technology Projects of China
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