Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase

Manal A. Farg, Kai Y. Soo, Adam K. Walker, Hong Pham, Jacqueline Orian, Malcolm K. Horne, Sadaf T. Warraich, Kelly L. Williams, Ian P. Blair, Julie D. Atkin

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Mutations in the gene encoding fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), but the mechanisms by which these mutants trigger neurodegeneration remain unknown. Endoplasmic reticulum (ER) stress is increasingly recognized as an important and early pathway to motor neuron death in ALS. FUS is normally located in the nucleus but in ALS, FUS redistributes to the cytoplasm and forms inclusions. In this study, we investigated whether FUS induces ER stress in a motor neuron like cell line (NSC-34). We demonstrate that ER stress is triggered in cells expressing mutant FUS, and this is closely associated with redistribution of mutant FUS to the cytoplasm. Mutant FUS also colocalized with protein disulfide-isomerase (PDI), an important ER chaperone, in NSC-34 cells and PDI was colocalized with FUS inclusions in human ALS lumbar spinal cords, in both sporadic ALS and mutant FUS-linked familial ALS tissues. These findings implicate ER stress in the pathophysiology of FUS, and provide evidence for common pathogenic pathways in ALS linked to the ER.

LanguageEnglish
Pages2855-2868
Number of pages14
JournalNeurobiology of Aging
Volume33
Issue number12
DOIs
Publication statusPublished - Dec 2012
Externally publishedYes

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Protein Disulfide-Isomerases
Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Sarcoma
Motor Neurons
Endoplasmic Reticulum
Spinal Cord
Cytoplasm

Cite this

Farg, Manal A. ; Soo, Kai Y. ; Walker, Adam K. ; Pham, Hong ; Orian, Jacqueline ; Horne, Malcolm K. ; Warraich, Sadaf T. ; Williams, Kelly L. ; Blair, Ian P. ; Atkin, Julie D. / Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase. In: Neurobiology of Aging. 2012 ; Vol. 33, No. 12. pp. 2855-2868.
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title = "Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase",
abstract = "Mutations in the gene encoding fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), but the mechanisms by which these mutants trigger neurodegeneration remain unknown. Endoplasmic reticulum (ER) stress is increasingly recognized as an important and early pathway to motor neuron death in ALS. FUS is normally located in the nucleus but in ALS, FUS redistributes to the cytoplasm and forms inclusions. In this study, we investigated whether FUS induces ER stress in a motor neuron like cell line (NSC-34). We demonstrate that ER stress is triggered in cells expressing mutant FUS, and this is closely associated with redistribution of mutant FUS to the cytoplasm. Mutant FUS also colocalized with protein disulfide-isomerase (PDI), an important ER chaperone, in NSC-34 cells and PDI was colocalized with FUS inclusions in human ALS lumbar spinal cords, in both sporadic ALS and mutant FUS-linked familial ALS tissues. These findings implicate ER stress in the pathophysiology of FUS, and provide evidence for common pathogenic pathways in ALS linked to the ER.",
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Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase. / Farg, Manal A.; Soo, Kai Y.; Walker, Adam K.; Pham, Hong; Orian, Jacqueline; Horne, Malcolm K.; Warraich, Sadaf T.; Williams, Kelly L.; Blair, Ian P.; Atkin, Julie D.

In: Neurobiology of Aging, Vol. 33, No. 12, 12.2012, p. 2855-2868.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Farg, Manal A.

AU - Soo, Kai Y.

AU - Walker, Adam K.

AU - Pham, Hong

AU - Orian, Jacqueline

AU - Horne, Malcolm K.

AU - Warraich, Sadaf T.

AU - Williams, Kelly L.

AU - Blair, Ian P.

AU - Atkin, Julie D.

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