Drosophila eye model to study the role of NAT9 in Alzheimer’s Disease related Dementia (ADRD)

Abstract

AbstractBackgroundOne of the hallmarks of Alzheimer’s disease (AD), an age‐related progressive form of dementia, is accumulation of the amyloid beta (Aβ42) plaque, which manifests in decline in cognitive function. 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.MethodWe 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.ResultThe gain‐of‐function of NAT9 rescues Aβ42‐mediated neurodegeneration whereas loss‐of‐function of NAT9 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.ConclusionOur data suggests that NAT9 downregulates JNK signaling pathway which can ameliorate Aβ42‐mediated neurodegeneration.