The Role of DIRAS Proteins in Neuronal Autophagy

神经变性是许多神经变性疾病的标志。尽管每一种神经退行性疾病 疾病通过不同的机制发展，其中许多疾病的共同特征是功能失调的自噬。 自噬是细胞清除其内容物的基本过程，如聚集的蛋白质， 细胞器，是维持神经元稳态的关键。缺乏自噬的小鼠会产生大量的 神经元的损失和蛋白质聚集体的积累，表明自噬对神经元的损伤是重要的。 功能然而，也有证据表明，一些自噬途径与细胞死亡有关， 这表明自噬在神经变性中的确切作用尚未完全解决。 DIRAS 1/2/3（DIRAS家族，GTP结合RAS样蛋白1/2/3），Ras超家族的成员， 调节癌细胞中的自噬。DIRAS蛋白通过作为自噬的一部分直接调节自噬 起始复合物和下调mTOR信号通路。重要的是，人类基因组包含 Diras 1、Diras 2和Diras 3;而小鼠基因组仅包含Diras 1和Diras 2，这强调了潜在的 人类和小鼠细胞之间的自噬差异。在初步研究中，我们发现 DIRAS 1和3增强自噬体的合成并与自噬体共定位于培养的 神经元我们假设，在神经元中，DIRAS蛋白可以被调节以增加神经保护作用， 自噬，促进神经元存活，并增强异常蛋白质和细胞器的清除。在 第一个目的，我们将研究DIRAS蛋白是否参与小鼠神经保护性或神经毒性自噬 和人类神经元。在第二个目标中，我们将研究DIRAS蛋白是否调节特定形式的 自噬，如线粒体自噬和细胞自噬。在第三个目标中，我们将确定DIRAS蛋白是否调节 易聚集蛋白质的降解。这些研究可以为“自噬增强”药物的开发奠定基础。 发现，并应用于许多神经退行性疾病，其中蛋白质清除功能障碍。

Neurodegeneration is a hallmark of many neurodegenerative disorders. Although each neurodegenerative disease develops via distinct mechanisms, a feature common to many of them is dysfunctional autophagy. Autophagy, the fundamental process by which cells clear their contents, such as aggregated proteins and organelles, is the key to maintaining neuronal homeostasis. Mice deficient in autophagy develop massive neuronal loss and the accumulation of protein aggregates, suggesting that autophagy is important for neuronal function. There is also evidence, however, that some autophagic pathways are associated with cell death, an indication that the precise role of autophagy in neurodegeneration has not been fully resolved. DIRAS1/2/3 (DIRAS family, GTP-binding RAS-like proteins 1/2/3), the members of the Ras superfamily, regulate autophagy in cancer cells. DIRAS proteins regulate autophagy directly by being a part of the autophagy initiation complex and downregulating the mTOR signaling pathway. Importantly, the human genome contains Diras1, Diras2, and Diras3; whereas the mouse genome contains only Diras1 and Diras2, underscoring potential autophagic differences between human and mouse cells. In preliminary studies, we found the expression of DIRAS1 and 3 enhances the synthesis of autophagosomes and co-localizes with autophagosomes in cultured neurons. We hypothesize that, in neurons, DIRAS proteins can be modulated to increase neuroprotective autophagy, promote neuronal survival, and enhance the clearance of abnormal proteins and organelles. In the first aim, we will investigate if DIRAS proteins are involved in neuroprotective or neurotoxic autophagy in mouse and human neurons. In the second aim, we will investigate if DIRAS proteins regulate the specific forms of autophagy such as mitophagy and pexophagy. In the third aim, we will determine if DIRAS proteins regulate degradation of aggregation-prone proteins. These studies could form the basis for “autophagy-enhancing” drug discovery, with applications to many neurodegenerative diseases in which protein clearance is dysfunctional.