Increased Expression of Endoplasmic Reticulum Stress-Related Signaling Pathway Molecules in Multiple Sclerosis Lesions

Abstract

Activation of endoplasmic reticulum (ER) stress-related cell signals has been reported in several neurologic disorders and may contribute to neurodegeneration. Endoplasmic reticulum stress is also linked to ischemic injury. However, activation of an ER stress response has not been investigated in multiple sclerosis (MS) lesions. We detected increased expression of ER stress-associated C/EBP homologous protein, immunoglobulin heavy chain-binding protein, and X-box-binding protein 1 in multiple cell types, including oligodendrocytes, astrocytes, T cells, and microglia in active MS lesions. Semiquantitative analysis of expression in active, chronic active, and chronic inactive lesions indicated that levels of immunoglobulin heavy chain-binding protein were significantly higher in acute lesions than in non-MS controls or MS normal-appearing white matter, and that ER stress-associated C/EBP homologous protein was upregulated to the greatest extent at the edges of chronic active lesions. Because demyelination may be triggered by a tissue response to ischemia-like conditions, changes in the hypoxia-related antigen D-110 were also investigated, and it was found that increased ER stress-associated C/EBP homologous protein expression can occur in either the presence or absence of D-110. A possible link between a perturbed ER and lesion development in MS suggests a signaling pathway that may represent a new therapeutic target in MS.

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Syncytin-1 was found to be more highly expressed in the glial cells of MS lesions, specifically in astrocytes and microglia (28). Moreover, Syncytin-1 has been shown to induce ER stress in astrocytes (23), in keeping with the observations from other groups suggesting ER stress is involved in MS-related disease mechanisms (29)(30)(31).…”

Redox regulation of cellular stress response in multiple sclerosis

“…In addition, cytokines, immunoglobulins, and complement complexes may elicit a survival response involving the induction of endogenous Hsps and other protective molecules, which indicates that redox dependent mechanisms in these cells are of great importance in MS [54][55][56]. The heat shock response contributes to establish a cytoprotective state in a variety of metabolic disturbances and injuries, including stroke, epilepsy, cell and tissue trauma, neurodegenerative disease, and aging [15,24].…”

Targeting the IRE1α–XBP1 branch of the unfolded protein response in human diseases

“…In another study using cell culture and mouse model of Parkinson’s disease, overexpression of spliced XBP1 demonstrated cytoprotection against 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death [42]. Moreover, elevated levels of XBP1 were also detected in multiple sclerosis demyelinated lesions [43]. …”