# The Regulation and Function of Neuron-Specific Alternative Splicing

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2022 · $378,742

## Abstract

Project Summary
Alzheimer’s disease (AD) is highly polygenic and much of its genetic architecture remains poorly understood.
Our current knowledge of AD molecular pathogenesis was mostly derived from studies of familial mutations of
early-onset AD. Near complete understanding of AD pathogenic mechanisms requires thorough investigation
of the still highly heritable late-onset AD (LOAD) and determination of disease relevant mechanisms. RNA
binding proteins (RBP) have emerged frequently involved in AD and AD associated dementia (ADRD).
Mutations in RBPs cause frontotemporal dementia. Dysfunction of RBPs and RNA processing are increasingly
implicated in pathology and progression of AD/ADRD. However, little is known about RBPs’ contributions to
AD. We have been studying the role of RNA binding protein PTBP2 in the brain for 14 years. This application is
built on our parental R01 award (R01NS104041) to extend our analyses of PTBP2 in the context of
Alzheimer’s Disease. Funded by the parental R01 award, our published works have demonstrated the
essential roles of PTBP2 and its regulatory targets in axonogenesis. Guided by our ongoing research and
unpublished data, we hypothesize that PTBP2 deficiency accelerates Alzheimer’s disease progression. To
investigate the PTBP2’s contribution to AD progression, we have started breeding Ptbp2 heterozygous mice
with 5xFAD mice expressing five AD familial mutations. We will determine whether PTBP2 deficiency
accelerates or exacerbates early manifestations of AD pathology. We will also develop resources including
aged compound mutants for studies of late-stage AD pathology. Our long history of researching PTBP2 in the
brain places us in a unique position to evaluate this hypothesis. The proposed research will be the prelude to
understanding the interactions between PTBP2, familial AD mutations, and other AD risk variants in AD
progression.

## Key facts

- **NIH application ID:** 10497373
- **Project number:** 3R01NS104041-05S1
- **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:** $378,742
- **Award type:** 3
- **Project period:** 2017-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497373

## Citation

> US National Institutes of Health, RePORTER application 10497373, The Regulation and Function of Neuron-Specific Alternative Splicing (3R01NS104041-05S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10497373. Licensed CC0.

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