ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-a, 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.

LanguageEnglish
Article numbere81170
Pages1-12
Number of pages12
JournalPLoS ONE
Volume8
Issue number11
DOIs
Publication statusPublished - 29 Nov 2013
Externally publishedYes

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Endoplasmic Reticulum Stress
DNA-binding proteins
Amyotrophic Lateral Sclerosis
DNA-Binding Proteins
endoplasmic reticulum
granules
Endoplasmic Reticulum
Cytoplasm
cytoplasm
Eukaryotic Initiation Factor-2
Drive
amyotrophic lateral sclerosis
Frontotemporal Lobar Degeneration
protein disulfide-isomerase
Protein Disulfide-Isomerases
mutants
dephosphorylation
Neuroblastoma
Pathology
spinal cord

Cite this

Walker, Adam K. ; Soo, Kai Y. ; Sundaramoorthy, Vinod ; Parakh, Sonam ; Ma, Yi ; Farg, Manal A. ; Wallace, Robyn H. ; Crouch, Peter J. ; Turner, Bradley J. ; Horne, Malcolm K. ; Atkin, Julie D. / ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. In: PLoS ONE. 2013 ; Vol. 8, No. 11. pp. 1-12.
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abstract = "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-a, 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.",
author = "Walker, {Adam K.} and Soo, {Kai Y.} and Vinod Sundaramoorthy and Sonam Parakh and Yi Ma and Farg, {Manal A.} and Wallace, {Robyn H.} and Crouch, {Peter J.} and Turner, {Bradley J.} and Horne, {Malcolm K.} and Atkin, {Julie D.}",
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ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. / Walker, Adam K.; Soo, Kai Y.; Sundaramoorthy, Vinod; Parakh, Sonam; Ma, Yi; Farg, Manal A.; Wallace, Robyn H.; Crouch, Peter J.; Turner, Bradley J.; Horne, Malcolm K.; Atkin, Julie D.

In: PLoS ONE, Vol. 8, No. 11, e81170, 29.11.2013, p. 1-12.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation

AU - Walker, Adam K.

AU - Soo, Kai Y.

AU - Sundaramoorthy, Vinod

AU - Parakh, Sonam

AU - Ma, Yi

AU - Farg, Manal A.

AU - Wallace, Robyn H.

AU - Crouch, Peter J.

AU - Turner, Bradley J.

AU - Horne, Malcolm K.

AU - Atkin, Julie D.

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AB - 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-a, 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.

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