USF-LVHN SELECT
Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1.
Publication/Presentation Date
2-1-2023
Abstract
Neuromuscular dysfunction is a common feature of mitochondrial diseases and frequently presents as ataxia, spasticity and/or dystonia, all of which can severely impact individuals with mitochondrial diseases. Dystonia is one of the most common symptoms of multiple mitochondrial dysfunctions syndrome 1 (MMDS1), a disease associated with mutations in the causative gene (NFU1) that impair iron-sulfur cluster biogenesis. We have generated Caenorhabditis elegans strains that recreated patient-specific point variants in the C. elegans ortholog (nfu-1) that result in allele-specific dysfunction. Each of these mutants, Gly147Arg and Gly166Cys, have altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility. We found that the Gly147Arg variant was hypersensitive to acetylcholine and that knockdown of acetylcholine release rescued nearly all neuromuscular phenotypes of this variant. In contrast, we found that the Gly166Cys variant caused predominantly postsynaptic acetylcholine hypersensitivity due to an unclear mechanism. These results are important for understanding the neuromuscular conditions of MMDS1 patients and potential avenues for therapeutic intervention.
Volume
16
Issue
2
ISSN
1754-8411
Published In/Presented At
Kropp, P. A., Rogers, P., Kelly, S. E., McWhirter, R., Goff, W. D., Levitan, I. M., Miller, D. M., & Golden, A. (2023). Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1. Disease models & mechanisms, 16(2), dmm049594. https://doi.org/10.1242/dmm.049594
Disciplines
Medical Education | Medicine and Health Sciences
PubMedID
36645076
Department(s)
USF-LVHN SELECT Program, USF-LVHN SELECT Program Students
Document Type
Article