# Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $379,178

## Abstract

In adult brains, neural progenitor/stem cells (NSCs) are responsible for the generation of new neurons
for the maintenance of the existing circuitry and after injuries. Deficiency in NSC maintenance and/or
neurogenesis contributes to both developmental defects and neurodegenerative diseases
for which aging is a major risk factor.
 The long-term goal of the proposed studies is to determine the molecular and cellular
mechanisms of NSC regulation in both young and aged animals, which can lead to the development of
effective therapies for neurodegenerative diseases. Autophagy is a highly conserved cellular process for
degradation of bulk cytoplasmic materials for maintenance of cellular homeostasis, and dysfunctions in
autophagy have been implicated in various diseases, including neurodegeneration and other age-related
disorders. FIP200 (FAK-family Interacting Protein of 200 kDa) was initially identified in our laboratory and
subsequently shown as one component of the ULK1/Atg13/FIP200 complex essential for the induction of
autophagy. In the previous funding period, we found that, deletion of Fip200, but not other autophagy genes
Atg5, Atg7 and Atg16L1, led to defective NSC maintenance and neurogenesis, suggesting a potential role for
the non-canonical function of FIP200 in NSC regulation through controlling p62 aggregate formation. In
additional prelim studies, we obtained rigorous genetic evidence that non-canonical function of FIP200 is
required for NSC maintenance and neurogenesis by generation and analyses of another unique mouse model
with FIP200-4A mutation in NSCs that blocks autophagy function of FIP200 specifically. Additionally, we found
that the FIP200 C-terminal region (FIP200-CT) could interact with p62, consistent with recent studies showing
its importance in degrading p62 aggregates. Moreover, we found that FIP200 can regulate TBK1 activation,
which can phosphorylate p62 to regulate its degradation, and that FIP200 also interacts with the TBK1 adaptor,
AZI2. In a second set of prelim studies, we analyzed the role of another autophagy gene Beclin1 in NSCs
employing new Becn1 KI mice and found that increased autophagy protected NSC pool and their neurogenesis
in aged Becn1 KI mice without affecting NSC in young mice. Lastly, we obtained additional prelim data
suggesting that oxidative stress may synergize with autophagy-deficiency to promote p62 aggregate formation.
Building upon these preliminary and prior studies, we propose to 1). investigate the mechanisms of non-canonical functions of FIP200 and potential synergy with its autophagy function in the regulation of NSCs, 2).
analyze the role and mechanisms of enhanced autophagy to prevent NSC pool decline and promote
neurogenesis in Becn1 KI mice, and 3). explore the role and mechanisms of NSC maintenance and
neurogenesis in autophagy-deficiency mice after oxidative insult and during aging. Together, these studies will
significantly advance our understanding of the regulation of NSC an...

## Key facts

- **NIH application ID:** 10434019
- **Project number:** 5R01NS094144-08
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** JUN-LIN GUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,178
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434019

## Citation

> US National Institutes of Health, RePORTER application 10434019, Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes (5R01NS094144-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434019. Licensed CC0.

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