Delineating the role of monocarboxylate transporter 8 (MCT8) in the context of neuroinflammation–mediated oligodendrocytopathy

Oligodendrocytes (OLs) myelinate central nervous system (CNS) axons and provide metabolic support to maintain axonal integrity. Thyroid hormone (TH) is a mitogen for oligodendroglial precursor cells (OPCs) maturation into myelinating OLs. Cellular uptake of TH is mediated by monocarboxylate transporter 8 (MCT8; encoded by slc16a2 ), and its dysfunction results in intracellular triiodothyronine (T3) deprivation, leading to hypomyelination and myelin degeneration during neuroinflammation. We showed that MCT8 expression is maintained in OPCs residing within the sub–ventricular zone (SVZ) throughout CNS development, suggesting a role during OL development. We identified MCT8 deficiency during neuroinflammatory and cuprizone demyelination models, as well as in secondary progressive multiple sclerosis (SPMS). These conditions were associated with dysregulated AKT–mTOR–PANK2 signaling and abrogated Co Enzyme A and lipid synthesis pathways in the CNS during myelin degeneration. Hence, neuroprotection during SPMS maybe achieved by overcoming MCT8 deficiencies in OLs.