Mechanisms of metabolic stress induced cell death of human oligodendrocytes: relevance for progressive multiple sclerosis

• Published in: Acta neuropathologica communications Vol. 11; no. 1; p. 108
• Main Authors: Fernandes, Milton Guilherme Forestieri, Mohammadnia, Abdulshakour, Pernin, Florian, Schmitz-Gielsdorf, Laura Eleonora, Hodgins, Caroline, Cui, Qiao-Ling, Yaqubi, Moein, Blain, Manon, Hall, Jeffery, Dudley, Roy, Srour, Myriam, Zandee, Stephanie E J, Klement, Wendy, Prat, Alexandre, Stratton, Jo Anne, Rodriguez, Moses, Kuhlmann, Tanja, Moore, Wayne, Kennedy, Timothy E, Antel, Jack P
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.07.2023; BioMed Central; BMC
• Subjects: Adenosine Triphosphate - metabolism; Antibodies; Apoptosis; Autophagy; Biochemistry; Brain research; Cell Death; Cell survival; Cells; Demyelination; Glucose; Humans; Metabolism; Multiple sclerosis; Multiple Sclerosis - pathology; Multiple Sclerosis, Chronic Progressive - pathology; Myelin; Neurodegeneration; Neurodegenerative disease; Oligodendroglia - pathology; Phosphates; Proteases; Reactive Oxygen Species - metabolism; Research ethics; RNA sequencing; Stress (Psychology); Stress management; Canada; United States > US; Montreal Quebec Canada; Neurodegenerative disease; Cell survival; Demyelination; Myelin; Neurodegeneration
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01601-1

Oligodendrocyte (OL) injury and loss are central features of evolving lesions in multiple sclerosis. Potential causative mechanisms of OL loss include metabolic stress within the lesion microenvironment. Here we use the injury response of primary human OLs (hOLs) to metabolic stress (reduced glucose/nutrients) in vitro to help define the basis for the in situ features of OLs in cases of MS. Under metabolic stress in vitro, we detected reduction in ATP levels per cell that precede changes in survival. Autophagy was initially activated, although ATP levels were not altered by inhibitors (chloroquine) or activators (Torin-1). Prolonged stress resulted in autophagy failure, documented by non-fusion of autophagosomes and lysosomes. Consistent with our in vitro results, we detected higher expression of LC3, a marker of autophagosomes in OLs, in MS lesions compared to controls. Both in vitro and in situ, we observe a reduction in nuclear size of remaining OLs. Prolonged stress resulted in increased ROS and cleavage of spectrin, a target of Ca -dependent proteases. Cell death was however not prevented by inhibitors of ferroptosis or MPT-driven necrosis, the regulated cell death (RCD) pathways most likely to be activated by metabolic stress. hOLs have decreased expression of VDAC1, VDAC2, and of genes regulating iron accumulation and cyclophilin. RNA sequencing analyses did not identify activation of these RCD pathways in vitro or in MS cases. We conclude that this distinct response of hOLs, including resistance to RCD, reflects the combined impact of autophagy failure, increased ROS, and calcium influx, resulting in metabolic collapse and degeneration of cellular structural integrity. Defining the basis of OL injury and death provides guidance for development of neuro-protective strategies.