The Role of DIRAS Proteins in Neuronal Autophagy

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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.