Date of Award
2026-05-01
Degree Name
Master of Science
Department
Biological Sciences
Advisor(s)
Kyung-An Han
Abstract
Alzheimer's disease and related dementias (ADRD) are progressive neurodegenerative diseases caused by genetic and non-genetic risk factors (e.g., aging, sleep loss, etc.). However, how these risk factors interact to cause ADRD is poorly understood. To assess this gap in knowledge, the Han lab performed a non-biased genetic screen using the model organism Drosophila melanogaster and identified novel dementia genes, including Scully (Scu) encoding a multifunctional mitochondrial enzyme, and Frequenin 1 (Frq1), encoding a neuronal calcium sensor. This thesis focused on characterizing these genes and identifying non-genetic risk factors interacting with them for ADRD endophenotypes, such as memory loss and impulsivity. To identify the cellular mechanism by which heterozygous mutations in Scu (Scu/+) cause aging-dependent memory loss and impulsivity, I examined the mitochondrial marker ATP synthase β subunit and redox-reporter expressed in the mushroom body (MB), the fly cognitive center mediating memory and impulsivity, and found that the mitochondria content and redox state of Scu/+ were comparable to those in control flies, regardless of age. I also found that sleep loss worsened Scu/+'s aging-dependent motor impulsivity, and the combined insult of sleep loss and aging in Scu/+ flies, but not in controls, led to increased redox sensitivity. These findings highlight how genetic and non-genetic risk factors interact for ADRD endophenotypes. Scu/+'s aging-dependent cognitive deficits were rescued by feeding ecdysone, the primary steroid hormone in flies, therefore we investigated whether the steroid hormone ecdysone contributes to ADRD endophenotypes. We first confirmed that heterozygous mutations in the ecdysteroidogenic enzyme gene spook (spo/+) resulted in reduced level of ecdysone in the brain, led to aging-dependent cognitive deficits, increased tau aggregation in the MB axons, and aggravated tau-induced cognitive impairments. This study is the first to showcase ecdysone as a neurosteroid and demonstrates its importance in ADRD-related tauopathy. In addition to Scu and spo, I investigated the novel dementia genetic factor Frq1 and found that heterozygous Frq1 flies exhibited reduced and fragmented sleep, which was further worsened by the presence of the dopamine transporter mutation. This work serves as a foundation for future studies exploring the mechanism by which Frq1 interacts with sleep anomaly and dopamine transporter for ADRD endophenotypes. Together, these studies reveal insights into ADRD mechanisms and provide evidence for potential interventions and therapeutic strategies targeting ADRD.
Language
en
Provenance
Received from ProQuest
Copyright Date
2026-05
File Size
115 p.
File Format
application/pdf
Rights Holder
Maya Solis
Recommended Citation
Solis, Maya, "Characterization Of Novel Dementia Genetic Risk Factors" (2026). Open Access Theses & Dissertations. 4803.
https://scholarworks.utep.edu/open_etd/4803