# Role of tau circular RNAs in tauopathies

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $191,250

## Abstract

Microtubule associated protein tau (encoded by the MAPT gene) is a critical component in the etiology of
Alzheimer's Disease (AD) and other tauopathies in which tau aggregates in neurofibrillary tangles.
However, the basic regulation of MAPT gene expression is still imperfectly understood. It is not clear
what causes the formation of neurofibrillary tangles, but tauopathic conditions show changes in tau
mRNA isoforms, generated through alternative pre-mRNA processing. Furthermore, mutations
changing alternative splicing of MAPT cause frontotemporal dementia, underscoring the importance of
tau pre-mRNA processing. We have identified human-specific circular RNAs (circRNAs) formed by the
tau-encoding mRNA from the MAPT locus generated by backsplicing of exon 10. Backsplicing forming
circRNAs occurs when pre-mRNA forms loops, which is aided by primate-specific Alu elements in
humans. The ground-breaking preliminary data demonstrate conclusive evidence of tau circRNAs
derived from human brain samples. We hypothesize that Alu elements help forming human specific
MAPT circRNAs, that likely after RNA methylation could be translated into proteins containing
multimers of microtubule binding sites. We will use (a) minigenes in tissue culture for molecular
mechanistic studies, to test whether MAPT circRNAs are translated into proteins after RNA methylation
and to test tau circRNA's interaction with other RNAs and proteins. These data will be correlated with
assessments in human brain tissue across the disease spectrum from pathologically-confirmed normal,
MCI (mild cognitive impairment), and AD cases. To (b) test tau circRNA's physiological relevance, we
have generated zebrafish lines expressing genomic parts of human MAPT that form circular RNAs in
neurons, and observed abnormal neurons after introduction of FTDP-17 mutants in constructs that
express only circRNAs. We will determine the expression of transgenic circRNAs, their encoded
proteins, possible sequestration of other RNAs and proteins, changes in neuron morphology, tau
pathology and correlate these data with spatial memory tests that take stress into account. These are
the first reports and studies of human tau circular RNAs. These studies are significant, as they could
provide a novel, human-specific molecular mechanism to alter MAPT gene expression, and possibly a
new mechanism to promote the formation of tau aggregates. Our studies capitalize on the excellent
brain bank at the University of Kentucky, headed by Co-I Dr. Nelson, and the zebrafish expertise of Co-
I Dr. Blackburn.

## Key facts

- **NIH application ID:** 9984228
- **Project number:** 5R21AG064626-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Stefan Stamm
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984228

## Citation

> US National Institutes of Health, RePORTER application 9984228, Role of tau circular RNAs in tauopathies (5R21AG064626-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9984228. Licensed CC0.

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