{"doi":"10.4103/1673-5374.368302","title":"Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown","abstract":"Oligodendrocytes are one of the most abundant cell types in the central nervous system (CNS) and act in close contact with neurons to assist with their cellular function and health (Kuhn et al., 2019). Oligodendrocytes play particular roles in rapid nerve impulse conduction through the wrapping of their myelinating projections around a nerve axon, as well as by offering trophic and metabolic support for the high energy expenditure of neurons. Additionally, oligodendrocytes have been found to regulate axonal health directly or indirectly by monitoring immune networks between glia and neurons. Unlike neurons, apoptotic mature oligodendrocytes can be replaced via differentiation from a pool of oligodendrocyte precursor cells (OPCs). Proliferative OPCs remain within the CNS throughout adulthood (Yalcin and Monje, 2021) and function as more than just a progenitor pool to replace lost myelinating oligodendrocytes. OPCs have been shown to interact with other oligodendrocytes, neurons, astrocytes, and microglia, and have roles in myelin maintenance, synaptic formation, blood-brain barrier support, and immune responses (Yalcin and Monje, 2021). These intercellular interactions, in addition to their capacity to become myelinating oligodendrocytes, could make OPCs an intriguing target for therapeutic intervention in demyelinating diseases, such as multiple sclerosis, and other neurodegenerative disorders with recent reports of white matter abnormalities and oligodendrocyte dysfunction (Philips et al., 2013; Ferrari Bardile et al., 2019; Errea and Rodriguez-Oroz, 2021; Kenigsbuch et al., 2022; Schuster et al., 2022). White matter degeneration has recently emerged as a shared pathology among many late-onset neurodegenerative diseases. Another pathological hallmark of these disorders is the intracellular aggregation of misfolded proteins, leading them to be commonly referred to as proteinopathies. These proteinopathy neurodegenerative diseases include Alzheimer’s disease (AD), tauopathies, Parkinson’s disease (PD), amyotrophic lateral sclerosis, and polyglutamine expansion diseases such as spinocerebellar ataxia type 3 (SCA3) and Huntington’s disease (HD). Protein aggregates have primarily been described in neurons within vulnerable brain regions of disease, leading to extensive study of pathomechanisms in affected neuronal populations. However, in the last decade or so, underexplored complex networks of interactions between oligodendrocytes and neurons in many neurodegenerative diseases have emerged. The complex networks of interactions between disease-associated oligodendrocytes and neurons lead to many interesting questions. Are disease-associated oligodendrocyte signatures a secondary effect of progressive neuronal degeneration? Could disease-associated oligodendrocytes be serving to signal cellular stress prior to overt cell loss of the precious post-mitotic neurons? Here, we present a perspective on the known and unknowns of disease-associated oligodendrocytes in neurodegenerative diseases. We touch briefly on the seminal findings that are leading to the breadth of disease-associated oligodendrocyte signatures across neurodegenerative diseases and highlight the tools that are being employed to elucidate the role of oligodendrocytes in disease (Figure 1). Finally, we cover the challenges towards progression in this developing field of study and proffer future directions to bridge the gaps that inform the role disease-associated oligodendrocytes might play in pathogenetic disease mechanisms, as well as the potential therapeutic opportunities.Figure 1: Toolkit for studying oligodendrocytes (OLs).(a–e) Tools for studying OLs in vivo. (a) Mouse models of disease can be crossed with OL lineage specific genetic reporters (i.e., fluorescent reporters) and Cre reporter lines for analysis of OL-specific perturbations. (b) Two/three-photon microscopy can be used in conjunction with OL-specific fluorescent reporter mouse models to explore longitu","journal":"Neural Regeneration Research","year":2023,"id":374581,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1136947,"name":"H McLoughlin","orcid":null,"position":1,"is_corresponding":false},{"id":932992,"name":"Kristen H. Schuster","orcid":"0000-0002-8896-3623","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:16:15.380731Z","pmid":"37056132","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}