Date on Master's Thesis/Doctoral Dissertation

8-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

Whittemore, Scott

Committee Co-Chair (if applicable)

Hetman, Michal

Committee Member

Samuelsen, Chad

Committee Member

McGee, Aaron

Committee Member

Rouchka, Eric

Author's Keywords

oligodendrocyte; autophagy; myelination; spinal cord injury; RNAseq; translatome

Abstract

Loss of myelin causes severe neurological disorders and functional deficits in white matter injuries (WMI) such as traumatic spinal cord injury (SCI). This dissertation is focused on autophagy in OL development and the OL translatome after SCI. Chapter I describes the history of myelin, OL development, and their involvement in neurodegenerative diseases and SCI. The proteostasis network, in particular autophagy, and its contributions to white matter pathology is discussed. It concludes examining advantages and disadvantages of unbiased omics tools, like RiboTag, to study transcriptional/translational landscapes after SCI. Chapter II focuses on autophagy in OPC/OL differentiation, survival, and proper myelination in the mouse brain during development. Conditional deletion of Atg5, an essential autophagy gene, in neonatal mice develop a tremor and is lethal. Further investigation revealed OPC apoptosis, reduced differentiation, and reduced myelination. Atg5-/- OPCs capable of differentiating failed to properly myelinate. Lastly, pharmacologically inhibiting or activating autophagy in OPC/dorsal root ganglion(DRG) co-cultures blocked and enhanced myelination, respectively. It is proposed autophagy is an important regulator in OPC survival, maturation, and myelination. Chapter III is focused on the OL translatome before and after SCI. Using RiboTag, the OL translatome was determined in the intact mouse spinal cord and 2, 10 and 42 days post contusive thoracic SCI. Biphasic upregulation of mitochondrial-respiration mRNAs at days 2 and 42 suggest OLs shift metabolism to oxidative phosphorylation. Pro-survival and cell death regulators peaked at day 2. Acute OL upregulation of the iron oxidoreductase Steap3, was confirmed at the protein level and further tested in vitro. It is proposed metabolic shift to oxidative phosphorylation may contribute to oxidative stress and exacerbated by proteins such as STEAP3. Collectively, autophagy is a critical regulator in OPC development and myelination and may facilitate myelin compaction. Such critical roles magnifies the importance of maintaining proteostasis, and its potential as a therapeutic target in white matter injuries. OL translatomic data suggests OLs response to SCI is dynamic, and metabolic shifts may indicate biphasic waves of oxidative stress. It also identifies new targets like Steap3 that have not previously been explored, proving a valuable dataset to explore OL response to SCI.

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