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The Role of Metabolism in a Drosophila Model of Neurofibromatosis 1 / Folasade A Sofela.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Sofela, Folasade A., author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Molecular biology.
- Genetics.
- Pharmacology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Cellular biology.
- Molecular biology.
- Genetics.
- Pharmacology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (105 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Intellectual disability (ID) is a prevalent condition affecting 2.5% of the global population, often presenting alongside sleep and circadian behavior disturbances. Neurofibromatosis 1 (NF1) serves as a prominent example of a monogenic intellectual disability syndrome (MIDS) which commonly leads to disrupted sleep behavior and has been recently associated with metabolic dysfunction. In this study, we investigated the sleep disturbances and metabolic dysfunctions associated with NF1 through metabolomic analysis of Drosophila Nf1 -null mutants. We found that these mutants display a metabolic signature indicative of starvation" characterized by diminished metabolites related to glucose, glycogen, and fatty acid metabolism, along with elevated mRNA levels of Akh, a hormone that stimulates foraging behavior during starvation. Sleep behavior was rescued by genetic manipulation of the AKH pathway and also by a high-sucrose diet, which also partially corrected hypolipidemia in Nf1-null mutants, suggesting that sleep loss is due to starvation-induced foraging. Interestingly, behavioral phenotypes can be recapitulated by loss of NF1 in the periphery and trace to mitochondrial defects that include elevated activity of the NADase SARM1. Indeed, inhibition of SARM1 activity rescues sleep behavior in Nf1 -null flies. These findings suggest a novel connection between loss of NF1 and mitochondrial dysfunction caused by SARM1 hyperactivation. Our work opens up new avenues for research into pharmacological and dietary interventions in NF1, and also potentially offer a schematic for investigation of the role of metabolism in other MIDS.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Sehgal, Amita; Jongens, Thomas A.; Committee members: Arany, Zoltan Pierre; Baur, Joseph A.; Bhoj, Elizabeth J. K.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381509915
- Access Restriction:
- Restricted for use by site license.
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