Loss of the Novel Myelin Protein CMTM5 in Multiple Sclerosis Lesions and Its Involvement in Oligodendroglial Stress Responses

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 16; p. 2085
• Main Authors: Zhan, Jiangshan, Gao, Yuanxu, Heinig, Leo, Beecken, Malena, Huo, Yangbo, Zhang, Wansong, Wang, Pingzhang, Wei, Tianzi, Tian, Ruilin, Han, Wenling, Yu, Albert Cheung Hoi, Kipp, Markus, Kaddatz, Hannes
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2023; MDPI
• Subjects: Analysis; Animal models; Animals; Antibodies; Autoimmune diseases; Autopsies; Care and treatment; Cellular stress response; Cerebellum; CMTM5; CRISPR; Cuprizone; Demyelination; Diagnosis; Encephalomyelitis; Endoplasmic reticulum; endoplasmic reticulum stress; ErbB-2 protein; Experimental allergic encephalomyelitis; experimental autoimmune encephalomyelitis; Gene expression; Genetic aspects; Laboratories; Multiple sclerosis; Myelin; Myelin proteins; Nervous system; Neurodegeneration; Oligodendrocytes; Physiology, Pathological; Proteins; Spinal cord; Substantia alba; Thapsigargin; China; United States > US; Netherlands; Germany
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12162085

This study comprehensively addresses the involvement of the protein CKLF-like Marvel transmembrane domain-containing family member 5 (CMTM5) in the context of demyelination and cytodegenerative autoimmune diseases, particularly multiple Sclerosis (MS). An observed reduction in CMTM5 expression in post-mortem MS lesions prompted further investigations in both in vitro and in vivo animal models. In the cuprizone animal model, we detected a decrease in CMTM5 expression in oligodendrocytes that is absent in other members of the CMTM protein family. Our findings also confirm these results in the experimental autoimmune encephalomyelitis (EAE) model with decreased CMTM5 expression in both cerebellum and spinal cord white matter. We also examined the effects of a Cmtm5 knockdown in vitro in the oligodendroglial Oli-neu mouse cell line using the CRISPR interference technique. Interestingly, we found no effects on cell response to thapsigargin-induced endoplasmic reticulum (ER) stress as determined by Atf4 activity, an indicator of cellular stress responses. Overall, these results substantiate previous findings suggesting that CMTM5, rather than contributing to myelin biogenesis, is involved in maintaining axonal integrity. Our study further demonstrates that the knockdown of Cmtm5 in vitro does not modulate oligodendroglial responses to ER stress. These results warrant further investigation into the functional role of CMTM5 during axonal degeneration in the context of demyelinating conditions.