Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis.
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.
Atkin
Julie D
JD
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia; Centre for Neuroscience, University of Melbourne, Australia. Electronic address: julie.atkin@florey.edu.au.
Farg
Manal A
MA
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Walker
Adam K
AK
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia; Centre for Neuroscience, University of Melbourne, Australia.
McLean
Catriona
C
Anatomical Pathology, Alfred Hospital, Commercial road, Prahan, Victoria, 3181, Australia.
Tomas
Doris
D
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Horne
Malcolm K
MK
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia; Centre for Neuroscience, University of Melbourne, Australia.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1