# The Role of DIRAS Proteins in Neuronal Autophagy

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $234,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10128894
- **Project number:** 1R21AG067282-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Andrey Tsvetkov
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128894

## Citation

> US National Institutes of Health, RePORTER application 10128894, The Role of DIRAS Proteins in Neuronal Autophagy (1R21AG067282-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10128894. Licensed CC0.

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