Drosophila Eye Model to Study the Role of Mnat9 in Alzheimer’s Disease-Related Dementia
Emily Snider, Prajakta Deshpande, Anuradha Chimata Venkatakrishnan; other authors: Madhuri Kango-Singh, Amit Singh
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is manifested as extracellular accumulation of amyloid-beta-42 (Aβ42) plaques and intracellular accumulation of neurofibrillary tangles (NFTs) due to hyperphosphorylation of tau that results in destabilization of microtubules. Targeted misexpression of human Aβ42 (GMR>Aβ42) in retinal neurons of developing Drosophila eye results in Aβ42 plaque(s) formation, extensive neurodegeneration and mimics AD like neuropathology. However, the underlying mechanism(s) for Aβ42-mediated neurodegeneration have not been fully understood. In a forward genetic screen, we identified microtubule associated N-acetyltransferase 9 (Mnat9) as one of the genetic modifiers of GMR>Aβ42 neurodegenerative phenotype. Mnat9 is known to stabilize microtubules by inhibiting c-Jun-N- terminal kinase (JNK) signaling. The neurodegenerative phenotype of GMR>Aβ42 is rescued by gain-of-function of Mnat9 whereas loss-of-function of Mnat9 exhibits converse phenotype of enhanced neurodegeneration. Human Mnat9 also suppresses Aβ42-mediated neurodegeneration suggesting the functional conservation. Surprisingly, Mnat9 neuroprotective function is independent of its acetylation activity. We found that Mnat9 downregulates JNK signaling pathway, which is involved in rescuing neurodegenerative phenotypes seen in GMR>Aβ42 background. Here we propose a new neuroprotective function of Mnat9 in downregulating JNK signaling pathway to ameliorate Aβ42-mediated neurodegeneration.
Primary Advisor's Department
Stander Symposium, College of Arts and Sciences
"Drosophila Eye Model to Study the Role of Mnat9 in Alzheimer’s Disease-Related Dementia" (2023). Stander Symposium Projects. 3138.