Date of Award
12-17-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Neurodegenerative diseases are characterized by selective neuronal vulnerability, a phenomenon in which a specific pathology induces the death of a particular subpopulation of neurons. For example, selective neuronal vulnerability in the peripheral nervous system results in sensory, motor, or mixed peripheral neuropathies. While the intrinsic differences between neuronal subtypes cannot fully explain the basis of selective neuronal vulnerability, it is plausible that it partially stems from neuron extrinsic mechanisms such as the malfunction of distinct Schwann cell (SC) subtypes. Recently, we identified an exciting subpopulation of myelinating SCs characterized by the expression of Adamtsl1, Cldn14, and Pmp2 (hereafter referred to as PMP2+ SCs), which forms very thick myelin around large-caliber axons, selectively enwraps motor axons, and is enriched in motor peripheral nerves. Additionally, the PMP2+ SC numbers are heavily decreased in the peripheral nerves of both ALS model mice and ALS patient nerves. Collectively, these findings suggest an enticing model that the malfunction of the newly identified PMP2+ SCs causes selective degeneration of motor axons. To address this model, we engineered a Pmp2-CreERT2 mouse and used it to express diphtheria toxin subunit A specifically in the PMP2+ SCs to assess their function. We found that the loss of PMP2+ SCs led to the immense loss of large-caliber motor axons and profound behavioral and electrophysiological defects. Excision of PMP2+ SCs subsequently induced regeneration in the peripheral nerves, leading to restoration of PMP2+ SCs and large-caliber motor axons and improvement of behavioral and electrophysiological readouts. Altogether, our findings highlight that the survival of large-caliber motor axons relies on the PMP2+ SCs, supporting the hypothesis that selective neuronal vulnerability can stem from inherent differences among distinct SC types.
Language
English (en)
Chair and Committee
Aaron DiAntonio
Committee Members
Brian Clark; Jeff Milbrandt; Sarah Ackerman; Ting Wang
Recommended Citation
Kozlowski, Mikolaj, "PMP2+ SCs maintain the survival and functioning of large-caliber motor axons" (2024). Arts & Sciences Electronic Theses and Dissertations. 3338.
https://openscholarship.wustl.edu/art_sci_etds/3338