# RNA regulation of intrinsically-determined neuronal properties

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2022 · $375,878

## Abstract

Project Summary
Neuronal cell death is the most consistent feature and ultimate cause of Alzheimer’s Disease and Alzheimer’s
Disease Related Dementia (AD/ADRD). It is urgent to determine the molecular changes and mechanisms
directly causing neuronal cell death in AD/ADRD, which will inform strategies to prevent neuronal loss in
neurodegenerative diseases. Increased apoptosis is evident in AD/ADRD. The pathogenesis mechanisms of
transitioning neurons from an apoptosis-resistant to an apoptosis-sensitive state are not well characterized.
Our research, funded by the parent award R01MH116220, has identified a neural-specific splicing regulatory
mechanism to suppress apoptosis in healthy neurons. The commitment step of apoptosis is activation of pro-
apoptotic protein BAK1 and/or BAX. We found BAK1 protein is substantially down-regulated during neuronal
differentiation due to neural-specific inclusion of BAK1 exon 5. BAK1 exon 5 splicing reduces the BAK1 protein
expression by inducing nonsense-mediated mRNA decay and unproductive translation of BAK1 transcripts. As
a result, neurons reduce apoptosis competence. Guided by promising preliminary data, we hypothesize that
neuronal splicing of BAK1 exon 5 is suppressed in AD/ADRD and that such suppression leads to increased
accumulation of BAK1 proteins and subsequent neurodegeneration. Our long history of researching neuronal
splicing and neuronal cell death places us in a unique position to evaluate this hypothesis. As dysregulated
RNA splicing emerges as an important molecular feature of AD/ADRD, a major knowledge gap remains
regarding the cellular consequences and biological outcomes of these dysregulated splicing events.
Successful completion of this project will provide the first concrete functional evidence for splicing
dysregulation as a pathogenesis mechanism of AD/ADRD.

## Key facts

- **NIH application ID:** 10497346
- **Project number:** 3R01MH116220-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Sika Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,878
- **Award type:** 3
- **Project period:** 2018-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497346

## Citation

> US National Institutes of Health, RePORTER application 10497346, RNA regulation of intrinsically-determined neuronal properties (3R01MH116220-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10497346. Licensed CC0.

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