Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis

Julie D. Atkin*, Manal A. Farg, Adam K. Walker, Catriona McLean, Doris Tomas, Malcolm K. Horne

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

272 Citations (Scopus)

Abstract

The unfolded protein response (UPR) is induced at symptom onset and disease end stage in rodent models of familial amyotrophic lateral sclerosis (ALS) that express superoxide dismutase (SOD1) mutations. However, ninety percent of human ALS is sporadic and mutations in SOD1 account for only 2% of total ALS. Here we show that a full UPR, including induction of stress sensor kinases, chaperones and apoptotic mediators, is also present in spinal cords of human patients with sporadic disease. Furthermore, the UPR chaperone protein disulphide isomerase (PDI) was present in CSF and was aggregated and widely distributed throughout the motor neurons of these patients. We also show up-regulation of UPR prior to the onset of symptoms in SOD1 rodents, implying an active role in disease. This study offers new insights into pathogenesis, placing ER stress onto a generic pathophysiology for ALS.

Original languageEnglish
Pages (from-to)400-407
Number of pages8
JournalNeurobiology of Disease
Volume30
Issue number3
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

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