Drosophila Eye Model to Study Genetic Modifiers of Alzheimer’s Disease
Date of Award
Ph.D. in Biology
Department of Biology
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. It is the most common form of dementia, affecting millions worldwide. AD is characterized by the accumulation of amyloid-beta (Aβ42) plaques and neurofibrillary tangles in the brain. While the exact causes of AD are still unclear, a combination of genetic, environmental, and lifestyle factors is believed to contribute to its development. The Drosophila model has become a valuable tool for studying AD due to its genetic conservation with humans, short lifespan, simple nervous system, and available genetic tools. In this study, we utilized a Drosophila model expressing human Aβ42 in the developing retina to investigate the underlying mechanisms of Aβ42-induced neurodegeneration. We conducted a genetic screen and identified several modifiers that significantly affected Aβ42-induced neurodegeneration. One of the modifiers we identified is N-acetyltransferase 9 (Mnat9), known for its role in stabilizing microtubules and inhibiting the c-Jun-N-terminal kinase (JNK) signaling pathway. Overexpression of Mnat9 rescued the neurodegenerative phenotype caused by Aβ42 accumulation, while loss-of-function enhanced neurodegeneration. Importantly, we found that the neuroprotective function of Mnat9 was independent of its acetylation activity. The transgenic expression of human NAT9 (hNAT9) in Drosophila also suppressed Aβ42-mediated neurodegeneration, suggesting functional conservation between Mnat9 and hNAT9 in interacting with JNK-mediated neurodegeneration. These findings uncover a novel neuroprotective role of Mnat9 in downregulating the JNK pathway to ameliorate Aβ42-induced neurodegeneration. Another modifier we identified is miR-277 (hsa-miR-3660 in humans). Loss-of-function of miR-277 enhanced neurodegeneration, while its gain-of-function rescued the phenotype. Overexpression of miR-277 in the presence of Aβ42 reduced cell death, preserved neuronal numbers, and restored axonal targeting defects. Through bioinformatic analysis, we identified head involution defective (hid), a proapoptotic gene, as one of the targets of miR-277. Overexpression of miR-277 significantly reduced hid transcript levels compared to the Aβ42 background alone. These findings reveal a neuroprotective mechanism of miR-277 by targeting hid and potentially other downstream effectors to modulate Aβ42-induced neurodegeneration. Our study also explored the interplay between the immune deficiency (IMD) pathway and the JNK pathway in Aβ42-mediated neurodegeneration. Activation of the IMD pathway, specifically the cleavage of Relish, enhanced Aβ42-induced neurodegeneration, while downregulation of relish rescued neurodegenerative phenotypes. Components of the IMD pathway, including dredd and Tak1, showed rescue effects when their activity was reduced. Interestingly, the activation of Relish in response to Aβ42-mediated neurodegeneration led to the degradation of Tak1, a critical component of the JNK pathway. This suggests that the IMD pathway can modulate Aβ42-induced neurodegeneration through its influence on the JNK pathway. Thus, our study identifies genetic modifiers, including Mnat9, miR-277, and components of the IMD and JNK pathways, that significantly affect Aβ42-induced neurodegeneration in a Drosophila model of AD. These findings provide insights into the underlying molecular mechanisms of Aβ42-induced neurodegeneration and offer potential therapeutic targets for future investigations. The Drosophila model serves as a valuable platform for studying AD pathology and developing novel therapeutic interventions. Further research on these genetic modifiers may contribute to the development of personalized medicine approaches for AD.
Alzheimer's disease, AD, cell death, Drosophila melanogaster, cell death, miR-277, Mnat9, JNK signaling, head involution defective
Copyright © 2023, Author
Deshpande, Prajakta Dhumraketu, "Drosophila Eye Model to Study Genetic Modifiers of Alzheimer’s Disease" (2023). Graduate Theses and Dissertations. 7260.