Protein disulfide isomerase disassembles stress granules and blocks cytoplasmic aggregation of TDP-43 in ALS

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimer’s patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimer’s patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid–liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. 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 patients and some Alzheimer’s patients.Teaser PDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 19. März Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Liu, Jia-Qi [VerfasserIn] Liu, Hao [VerfasserIn] Li, Yuying [VerfasserIn] Liu, Xiangyi [VerfasserIn] Wang, Li-Qiang [VerfasserIn] Wang, Kan [VerfasserIn] Yang, Zhaofei [VerfasserIn] Fu, Qi [VerfasserIn] Xu, Xiaojiao [VerfasserIn] Chen, Jie [VerfasserIn] Zhang, Yingshuang [VerfasserIn] Zhou, Jun [VerfasserIn] Lei, Weidong [VerfasserIn] Cui, Mengchao [VerfasserIn] Liang, Yi [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.03.16.585334

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PPN (Katalog-ID):	XBI042940109