Publication Date
2023
Document Type
Dissertation
Committee Members
Keiichiro Susuki, M.D., Ph.D. (Advisor); Thomas L. Brown, Ph.D. (Committee Member); David R. Ladle, Ph.D. (Committee Member); Shulin Ju, Ph.D. (Committee Member); Michael P. Markey, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Myelin formed around axons ensures rapid and efficient action potential propagation. Disruption of myelinated axons in the peripheral nervous system (PNS) often causes nerve conduction failure, neurological symptoms and can lead to long-term disability. Calpains are calcium dependent cysteine proteases that play many roles during both normal physiology and pathogenesis. Calpain-1 (CAPN1) and calpain-2 (CAPN2) are key calpain paralogs found in the nervous system and potentially have opposing roles, with CAPN2 having a more neurodegenerative function. In the central nervous system (CNS), calpains have a role in developmental myelination as well as in the pathological demyelination of multiple sclerosis and neurodegeneration. However, less is known about calpain’s role in myelination and injuries in the PNS. Here, we show a transient increase of activated CAPN1 in postnatal rat sciatic nerves when myelin is actively formed. Expression of the endogenous calpain inhibitor calpastatin steadily decreased during postnatal development. In lysolecithin-induced acute demyelination of adult rat sciatic nerves, we show an increase of CAPN1 and decrease of calpastatin expression. These changes in the calpain-calpastatin system are distinct from those during CNS development or during acute axonal degeneration in peripheral nerves. Since CAPN2 is the most highly expressed calpain in sciatic nerves, we next created novel transgenic mice lacking CAPN2 in myelinating glial cells (Cnp-Cre;Capn2f/f). Compared with littermate controls, these mice show no overt phenotype, displaying normal grip strengths and motor nerve conduction velocities along sciatic nerves. Using immunohistochemistry, node of Ranvier and myelin structures appear normal in the sciatic nerves. Additionally, we show that CAPN2 appears dispensable in the Schwann cell repair phenotype for recovery up to 21 days post crush (DPC) injury of the sciatic nerve. Finally, using mice overexpressing the calpain inhibitor calpastatin, we demonstrate a slower recovery and regeneration of nodes of Ranvier up to 21 DPC injury of the sciatic nerve. Overall, our results suggest that the calpain-calpastatin system is involved in demyelinating and axonal degeneration disease mechanisms in the PNS, and we have generated and characterized a mutant mouse line that will be a valuable tool in examining the role of Schwann cell CAPN2 in disease models.
Page Count
115
Department or Program
Biomedical Sciences
Year Degree Awarded
2023
Copyright
Copyright 2023, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0005-7770-1336
