Biology and Biomedical Sciences: Neurosciences
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Mitochondrial dysfunction has emerged as a common cause of peripheral neuropathies. While the role of neuronal and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell: SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Greater insight into the biology and pathology of SC mitochondrial metabolism could be relevant to the treatment of peripheral neuropathies, particularly because SCs critically support axonal stability and function as well as promote peripheral nerve regeneration. The present thesis investigates the contribution of SC mitochondrial deficits to disease progression in peripheral neuropathies as well as the gene regulatory network that drives the SC regenerative response after injury and in disease states. We describe the generation and characterization of the first mouse model useful in directly interrogating the contribution of SC mitochondrial dysfunction to peripheral neuropathy. These mice: Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene: Tfam), which is required for mtDNA transcription and replication. Interestingly, induction of SC-specific mitochondrial dysfunction did not affect SC survival; instead, these deficits resulted in a severe, progressive peripheral neuropathy characterized by extensive axonal degeneration that recapitulated critical features of human neuropathy. Mechanistically, we demonstrated that SC mitochondrial dysfunction activates a maladaptive integrated stress response and causes a shift in lipid metabolism away from new lipid biosynthesis towards increased lipid oxidation. These alterations in lipid metabolism caused the early depletion of key myelin lipid components as well as a dramatic accumulation of acylcarnitine lipid intermediates. Importantly, release of acylcarnitines from SCs was toxic to axons and induced their degeneration. Our results show that normal mitochondrial function in SCs is essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies. Moreover, our work identifies alterations in SC lipid metabolism and the accumulation of toxic lipid intermediates as novel mechanisms driving some of the pathology in peripheral neuropathies associated with mitochondrial dysfunction. Tfam-SCKO mice showed a severe deficiency in their ability to remyelinate peripheral nerve axons after injury. To gain insight into the highly orchestrated process of SC-mediated support of axonal regeneration, we also investigated the transcriptional and post-transcriptional gene regulatory program that drives the SC regenerative response. We profiled the expression of SC microRNAs: miRNAs) after peripheral nerve lesions as well as characterized the injury response of SCs with disrupted miRNA processing and showed that SC miRNAs modulated the injury response largely by targeting positive regulators of SC dedifferentiation/proliferation. SC miRNAs cooperated with transcriptional regulators to promote rapid and robust transitions between the distinct differentiation states necessary to support nerve regeneration. Moreover, we identified miR-34a and miR-140 as regulators of SC proliferation and myelination. We then used a novel computational approach to infer the gene regulatory network involved in this SC injury response and gain insight on cooperative regulation of this process by transcription factors and miRNAs. Together, the results described in the present thesis represent a significant increase in our understanding of how mitochondrial abnormalities specifically in SCs contribute to clinical impairment in patients with peripheral neuropathy. Moreover, the mechanistic characterization of lipid metabolism abnormalities in SCs following mitochondrial dysfunction elucidates potentially important therapeutic targets. Finally, our analysis of the transcriptional and post-transcriptional gene regulatory network involved in the SC regenerative response also provides valuable insight that could be harnessed to help restore normal nerve function in patients with peripheral neuropathy.
Viader, Andreu, "The Role of Schwann Cell Mitochondrial Metabolism in Schwann Cell Biology and Axonal Survival" (2011). All Theses and Dissertations (ETDs). 659.
Permanent URL: http://dx.doi.org/10.7936/K7319SXJ