Journal Article

ALS-Associated TDP-43 Induces Endoplasmic Reticulum Stress, Which Drives Cytoplasmic TDP-43 Accumulation and Stress Granule Formation

Farg, Manal A., Walker, Adam K., Sundaramoorthy, Vinod, Turner, Bradley J., Wallace, Robyn H., Crouch, Peter J., Horne, Malcolm K., Atkin, Julie D., Ma, Yi, Parakh, Sonam, Soo, Kai Y.

2013

نظرة عامة

In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.

• الناشر: Public Library of Science,Public Library of Science (PLoS)
• موضوع: Active Transport, Cell Nucleus - drug effects / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animals / Apoptosis / Biochemistry / Cell culture / Cell Line / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Cellular stress response / Cinnamates - pharmacology / Compartments / Cords / Cytoplasm / Cytoplasm - drug effects / Cytoplasm - metabolism / Degeneration / Deoxyribonucleic acid / Dephosphorylation / DNA / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Frontotemporal dementia / Golgi apparatus / Golgi Apparatus - drug effects / Golgi Apparatus - metabolism / Granular materials / Humans / Inclusions / Lysates / Mental health / Mice / Mutation / Neuroblastoma / Neuroblastoma cells / Neuroblasts / Neuronal-glial interactions / Neurosciences / Overexpression / Oxidative stress / Pathology / Pharmacology / Phosphorylation / Protein Disulfide-Isomerases - metabolism / Proteins / Recruitment / Rodents / Science / Spinal Cord - metabolism / Stress / Stresses / Thiourea - analogs & derivatives / Thiourea - pharmacology / Transcription factors / Transgenic mice