The Essential Role of de Novo Fatty Acid Synthesis in CNS Myelin Regeneration

Abstract

A variety of pathological conditions of the central nervous system (CNS) are associated with demyelination and loss of myelinating oligodendrocytes, e.g. spinal cord injury, stroke, and primary demyelinating diseases such as multiple sclerosis (MS). Common to all of these pathologies is the intrinsic, yet variable, capacity of the CNS to regenerate damaged myelin sheaths, resulting in the restoration of saltatory conduction and neuroprotection. Although remyelination can be initially extensive, it characteristically fails in long-standing, chronic demyelinating pathologies, such as MS. Remyelination in the CNS is primarily mediated by a pool of adult progenitor cells, the oligodendrocyte progenitor cells (OPCs). Upon demyelination, these highly proliferative and migratory progenitors are activated and recruited to the lesion site, where they differentiate into oligodendrocytes and form new myelin sheaths around denuded axons. Proliferation of adult OPCs and subsequent differentiation into myelinating cells during remyelination requires a tremendous increase in cell size and cellular membranes, hence calling for a vast surge in lipid availability. Fatty acids are the primary apolar building blocks for complex membrane lipids, and thus myelin itself. Moreover, fatty acids are critical to a variety of fundamental cellular processes, including membrane targeting of proteins, energy storage, cell signaling and transcriptional regulation. Most cells are thought to primarily rely on uptake to maintain their fatty acids pool, but highly metabolically active and proliferative, e.g. precursor/stem cells are strongly dependent on de novo synthesis mediated by fatty acid synthase (FASN). The multifunctional enzyme FASN is strictly required for de novo synthesis of fatty acids, mostly palmitate. Tissue-specific ablation of FASN in various cell types has provided valuable insights into the diverse and largely cell type- specific functions of de novo fatty acid synthesis. Given the highly proliferative nature of OPCs and the tremendous demand for lipids towards membrane synthesis during remyelination, we hypothesized endogenous fatty acid synthesis in OPCs to be critical in these processes. To this end, we induced FASN depletion in adult OPCs to assess its requirement for OPC proliferation, differentiation, and remyelination, following experimental gliotoxin-induced demyelination. We show that FASN is very low expressed in OPCs, but strongly expressed in oligodendrocytes differentiated from adult OPCs during remyelination. Consistently, FASN-activity is dispensable for adult OPC proliferation and maintenance during remyelination. Most importantly, we found FASN activity is critical for efficient CNS remyelination, an effect that is at least in part dependent on the requirement of FASN-mediated de novo fatty acid synthesis for maintaining the adult OPC-derived oligodendrocyte population during remyelination. Our results add valuable information to the understanding of the regulation of the remyelination process in demyelinating conditions, a promising currently pursued drug target.