Expression profiles of endoplasmic reticulum stress-related molecules in demyelinating lesions and multiple sclerosis

Abstract

Background: Increasing evidence associates the endoplasmic reticulum (ER) stress signalling pathway as a potential treatment target in multiple sclerosis (MS). Objective: To establish the expression profile of markers of ER stress both in demyelinating biopsy specimens and microdissected lesions in human post-mortem MS tissue. Methods: Immunohistochemical detection of C/EBP homologous protein (CHOP), immunoglobulin heavy chain binding protein (BiP), and hypoxia marker antigen D-110 in biopsies from three patients with MS primary or secondary progressive, three patients with clinically isolated syndrome, and one patient with lesional epilepsy was carried out. Laser capture microdissection of normal, perilesion and lesion tissue from post-mortem MS tissue and non-diseased control tissue was performed, followed by real-time PCR to detect ER stress genes. Results: In biopsy specimens, increased expression of the ER and hypoxic stress molecules in a range of cell types in most of the actively demyelinating lesions and perilesions was detected. Real-time PCR analysis demonstrated statistically significant elevated expression of the ER stress genes in normal-appearing white matter relative to control white matter. Moreover, significantly increased expression of CHOP was detected in the perilesion of active plaques ( p < 0.01). Conclusions: Our results, showing detection of elevated expression of ER stress molecules in lesional tissue, offer compelling evidence for further investigation of the ER stress signalling pathway as a potential therapeutic target for the treatment of MS.