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. and Atkin, Julie D. (2012) Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase. Neurobiology of Aging, 33 12: 2855-2868. doi:10.1016/j.neurobiolaging.2012.02.009


Author 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.
Title Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase
Journal name Neurobiology of Aging   Check publisher's open access policy
ISSN 0197-4580
1558-1497
Publication date 2012-12-01
Sub-type Article (original research)
DOI 10.1016/j.neurobiolaging.2012.02.009
Open Access Status Not yet assessed
Volume 33
Issue 12
Start page 2855
End page 2868
Total pages 14
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Subject 2800 Neuroscience
1302 Ageing
2728 Clinical Neurology
1309 Developmental Biology
2717 Geriatrics and Gerontology
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.
Keyword Amyotrophic lateral sclerosis
Endoplasmic reticulum stress
FUS fused in sarcoma
Protein disulfide-isomerase
Translocated in liposarcoma
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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