PMID- 33807572 OWN - NLM STAT- MEDLINE VI - 10 IP - 3 TI - Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - Switzerland TA - Cells JT - Cells JID - 101600052 IS - 2073-4409 (Electronic) LID - 565 [pii] LID - 10.3390/cells10030565 [doi] FAU - Raffaele, Stefano AU - Raffaele S AUID- ORCID: 0000-0002-2734-5418 AD - Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy. FAU - Boccazzi, Marta AU - Boccazzi M AUID- ORCID: 0000-0003-0844-1030 AD - Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy. FAU - Fumagalli, Marta AU - Fumagalli M AUID- ORCID: 0000-0002-0158-842X AD - Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy. IS - 2073-4409 (Linking) SB - IM MH - Amyotrophic Lateral Sclerosis/*physiopathology MH - Humans MH - Oligodendroglia/*metabolism OTO - NOTNLM OT - *GPR17 receptor OT - *amyotrophic lateral sclerosis (ALS) OT - *glial cells OT - *monocarboxylate transporter 1 (MCT1) OT - *neurodegenerative disease OT - *oligodendrocyte precursor cells (OPCs) OT - *oligodendrocytes OT - *regenerative medicine OT - *remyelination PMC - PMC8000560 DCOM- 20211119 LR - 20211119 DP - 20210305 DEP - 20210305 AB - Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.