Author ORCID Identifier

https://orcid.org/0000-0001-6303-1080

Date of Award

Fall 9-6-2023

Document Type

Thesis (Ph.D.)

Department or Program

Biological Sciences

First Advisor

Robert A. Hill

Abstract

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining intravital imaging with a single-cell ablation technique called 2Phatal. Oligodendrocyte 2Phatal activated a stereotyped degeneration cascade which triggered remyelination by local OPCs. Remyelination efficiency was dependent on initial myelin patterns and dynamic imaging revealed rapid repair with near-seamless transitions between myelin loss and remyelination, a process we call synchronous remyelination. A subset of highly branched OPCs executed this remyelination, pointing towards demyelination-associated morphological signatures of fate. Age-related demyelination mirrored the degenerative cascade observed with 2Phatal; however, remyelination in aging was defective due to failed oligodendrogenesis. Thus, oligodendrocyte 2Phatal uncovered novel forms of rapid remyelination that restore myelin patterns in the adult but are absent in aging. We go on to demonstrate that the maturation state of oligodendrocytes determines the dynamics and mechanism of cell death. Premyelinating and newly formed oligodendrocytes degenerate more rapidly than mature oligodendrocytes, but faster than OPCs, following 2Phatal. Furthermore, they appear to utilize a caspase-dependent form of cell death, while mature oligodendrocytes do not. This new insight suggests that different cell death mechanisms are used by these two populations, necessitating distinct strategies to protect preestablished and new oligodendrocytes in human aging and/or disease.

Original Citation

Chapman, T.W., Olveda, G.E., Bame, X. et al. Oligodendrocyte death initiates synchronous remyelination to restore cortical myelin patterns in mice. Nat Neurosci 26, 555–569 (2023). https://doi.org/10.1038/s41593-023-01271-1

Download

Share

COinS