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

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...

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Bibliographic Details
Published in:Neurobiology of disease 2008-06, Vol.30 (3), p.400-407
Main Authors: Atkin, Julie D, Farg, Manal A, Walker, Adam K, McLean, Catriona, Tomas, Doris, Horne, Malcolm K
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Animals
Animals, Genetically Modified
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum - physiology
Female
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Neurology
Oxidative Stress - physiology
Protein Folding
Rats
Rats, Sprague-Dawley
Superoxide Dismutase - biosynthesis
Superoxide Dismutase - genetics
Superoxide Dismutase-1
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Summary: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.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2008.02.009