Drosophila eye model to study the role of NAT9 in Alzheimer’s Disease related Dementia (ADRD)
Prajakta D. Deshpande, Emily M. Snider
Alzheimer's Disease (AD), an age-related progressive form of dementia, is characterized by a decline in cognitive function. Accumulation of amyloid beta (Aβ42) plaques is one of the characteristics of AD. The accumulation of these Aβ42 plaques trigger the hyperphosphorylation of tau, a microtubule associated protein, which results in the intracellular accumulation of neurofibrillary tangles (NFTs) due to destabilization of microtubules. We employed the Gal4/UAS system in Drosophila melanogaster to misexpress human Aβ42 within the developing fly retina, exhibiting AD-like neuropathology. Accumulation of Aβ42 plaque(s) triggers the aberrant activation of signaling pathways like the JNK pathway resulting in neuronal cell death by unknown mechanism(s). Using candidate based forward genetic screening, we identified N-acetyltransferase 9 (NAT9) as one of the genetic modifiers of GMR>Aβ42 reduced eye phenotype. Previously NAT9 has been shown to stabilize microtubules by acetylation of tubulins, thereby inhibiting JNK signaling. This study aims to understand the role of NAT9 in Aβ42-mediated neurodegeneration. The gain-of-function of NAT9 in GMR>Aβ42 background suppresses the Aβ42-mediated neurodegeneration whereas loss-of-function of NAT9 in GMR>Aβ42 background enhances Aβ42-mediated neurodegeneration. We have also found that the gain-of-function of human NAT9 also suppresses Aβ42-mediated neurodegeneration suggesting the functional conservation. Interestingly, mutated NAT9 in the acetyl- CoA binding site shows similar phenotype as gain-of-function of NAT9 suggesting its function is independent of acetylation activity. Moreover, the eye antennal imaginal discs of loss-of-function of NAT9 in GMR>Aβ42 background shows the activation of JNK pathway by increased pJNK levels. Hence, here we propose that NAT9 downregulates JNK signaling pathway which can ameliorate Aβ42-mediated neurodegeneration.
Primary Advisor's Department
Stander Symposium project, College of Arts and Sciences
United Nations Sustainable Development Goals
Good Health and Well-Being
"Drosophila eye model to study the role of NAT9 in Alzheimer’s Disease related Dementia (ADRD)" (2022). Stander Symposium Projects. 2430.