# Identifying and understanding the role of repeat RNAs and RAN proteins in Alzheimer's disease

> **NIH NIH K99** · UNIVERSITY OF FLORIDA · 2021 · $76,719

## Abstract

PROJECT SUMMARY/ABSTRACT (30 lines of text):
Alzheimer’s disease, the most common form of dementia, is characterized by cognitive decline and impairment
of behavioral and functional abilities. Approximate 5.8 million people in the United States are affected by
Alzheimer’s disease (AD) and this number is anticipated to triple by 2050. While mutations in amyloid
precursor protein (APP) and presenillin (PSEN1 and PSEN2) are known to cause familial early onset AD and
the APOE4 variant is a well-known disease risk factor, the genetic contributions to the majority of late onset
AD cases are not clear. Additionally, while the accumulation of Aβ plaques and hyperphosphorylated tau are
considered to be hallmark features of AD cases, Aβ plaques and tau tangles do not fully explain the clinical
features and heterogeneity found in AD patients. The identification of the C9orf72 GGGGCC hexanucleotide
repeat expansion as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal
dementia raises an intriguing question whether unidentified repeat expansion mutations contribute to other
form of dementia including AD. Additionally, similarities in disease pathology are observed between AD and
patients with repeat expansion disorders. These similarities include the accumulation of abnormal proteins,
neuronal loss in affected brain regions, and the involvement of stress in worsening disease. While repetitive
elements account for a large portion of the human genome, the detection repeat-expansion mutations,
especially GC-rich repeat expansions, is challenging. To overcome the difficulties in identifying repeat
expansion mutations, I have developed a novel dCas9-based repeat pull-down method (dCas9READ) that
allows the isolation of repeat expansion mutations directly from the genomic DNA of individual patients. The
objective of this proposal is to test the hypothesis that novel repeat expansion mutations contribute to late
onset AD and their repeat containing RNA and RAN products are toxic and contribute to AD pathology. I am
excited to report that in an initial screen, 17.5% of human AD autopsy cases tested were positive for RAN
protein aggregates and RNA foci. In this grant, I will follow-up on these exciting preliminary data and test this
hypothesis that novel repeat expansion mutations contribute to AD in the following specific aims: Aim 1) Will
develop a novel dCas9-based technique for rapidly identifying repeat expansions. Aim 2) Will test the
hypothesis that novel repeat expansions mutations are present at higher frequencies in late onset AD vs.
control samples. Aim 3) Will test the hypothesis that novel repeat expansion mutations are toxic and contribute
to AD pathology.

## Key facts

- **NIH application ID:** 10263228
- **Project number:** 5K99AG065511-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Lien Nguyen
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,719
- **Award type:** 5
- **Project period:** 2020-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263228

## Citation

> US National Institutes of Health, RePORTER application 10263228, Identifying and understanding the role of repeat RNAs and RAN proteins in Alzheimer's disease (5K99AG065511-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10263228. Licensed CC0.

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