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

NEUROBIOLOGY OF DISEASE

卷:30

Article

Atkin, Julie D.^2,3  Farg, Manal A.³  Walker, Adam K.^2,3  McLean, Catriona¹  Tomas, Doris³  Horne, Malcolm K.^2,3 

[1] Alfred Hosp, Prahran, Vic 3181, Australia

[2] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia

[3] Univ Melbourne, Howard Florey Inst, Parkville, Vic 3052, Australia

关键词: sporadic amyotrophic lateral sclerosis (ALS);    endoplasmic reticulum (ER) stress;    unfolded protein response (UPR);    neurodegeneration;    protein disulfide isomerase (PDI);    motor neuron disease (MND);   

DOI  :  10.1016/j.nbd.2008.02.009

来源: Elsevier

【 摘 要 】

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. (C) 2008 Elsevier Inc. All rights reserved.

【 授权许可】

Free