N-Acetyltransferase 9 ameliorates Aβ42-mediated neurodegeneration in the Drosophila eye.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, manifests as accumulation of amyloid-beta-42 (Aβ42) plaques and intracellular accumulation of neurofibrillary tangles (NFTs) that results in microtubule destabilization. Targeted expression of human Aβ42 (GMR > Aβ42) in developing Drosophila eye retinal neurons results in Aβ42 plaque(s) and mimics AD-like extensive neurodegeneration. However, there remains a gap in our understanding of the underlying mechanism(s) for Aβ42-mediated neurodegeneration. To address this gap in information, we conducted a forward genetic screen, and identified N-acetyltransferase 9 (Mnat9) as a genetic modifier of GMR > Aβ42 neurodegenerative phenotype. Mnat9 is known to stabilize microtubules by inhibiting c-Jun-N- terminal kinase (JNK) signaling. We found that gain-of-function of Mnat9 rescues GMR > Aβ42 mediated neurodegenerative phenotype whereas loss-of-function of Mnat9 exhibits the converse phenotype of enhanced neurodegeneration. Here, we propose a new neuroprotective function of Mnat9 in downregulating the JNK signaling pathway to ameliorate Aβ42-mediated neurodegeneration, which is independent of its acetylation activity. Transgenic flies expressing human NAT9 (hNAT9), also suppresses Aβ42-mediated neurodegeneration thereby suggesting functional conservation in the interaction of fly Mnat9 or hNAT9 with JNK-mediated neurodegeneration. These studies add to the repertoire of molecular mechanisms that mediate cell death response following accumulation of Aβ42 and may provide new avenues for targeting neurodegeneration.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，表现为β - 淀粉样蛋白 - 42（Aβ42）斑块的积聚以及神经原纤维缠结（NFTs）在细胞内的积聚，从而导致微管不稳定。在发育中的果蝇眼视网膜神经元中靶向表达人Aβ42（GMR＞Aβ42）会导致Aβ42斑块形成，并模拟出类似AD的广泛神经退行性变。然而，我们对Aβ42介导神经退行性变的潜在机制的理解仍存在差距。为了填补这一信息缺口，我们进行了正向遗传筛选，并确定N - 乙酰转移酶9（Mnat9）是GMR＞Aβ42神经退行性表型的遗传修饰因子。已知Mnat9通过抑制c - Jun - N - 末端激酶（JNK）信号传导来稳定微管。我们发现Mnat9的功能获得可挽救GMR＞Aβ42介导的神经退行性表型，而Mnat9的功能缺失则表现出相反的神经退行性增强的表型。在此，我们提出Mnat9具有一种新的神经保护功能，即通过下调JNK信号通路来改善Aβ42介导的神经退行性变，且该功能与其乙酰化活性无关。表达人NAT9（hNAT9）的转基因果蝇也能抑制Aβ42介导的神经退行性变，这表明果蝇Mnat9或hNAT9在与JNK介导的神经退行性变的相互作用中具有功能保守性。这些研究丰富了介导Aβ42积聚后细胞死亡反应的分子机制，可能为针对神经退行性变提供新的途径。