# New Targets in C9orf72 FTD: Exploring Histone H3 S10 Phosphorylation

> **NIH NIH R15** · BROOKLYN COLLEGE · 2022 · $471,000

## Abstract

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that has been linked to disruptions
in many genes. FTD belongs to a group of dementias catalogued as Alzheimer's Disease Related Dementias
(ADRD). Hexanucleotide repeat expansions in Chromosome 9 Open Reading Frame 72 (C9orf72) are the most
common genetic alteration linked to FTD. However, the precise mechanisms linking C9orf72 expansions to
neurotoxicity remain incompletely characterized.
 Histones are the protein scaffold of chromatin. Their post-translational modification can alter gene
expression. Our preliminary data support a model of interplay between protein aggregation and histone
modifications, a notion that is not well characterized in FTD. We propose the overarching hypothesis that the
toxic effect of protein aggregation is related to altered histone marks and altered gene expression. We reveal a
genome-wide increase in the phosphorylation of Histone H3 on Serine 10 (H3S10ph), mediated by Aurora B
kinase, as an important modification associated with C9orf72 expansions. We propose that C9orf72 mutations
lead to increased activity Aurora B kinase in the nucleus which in turn leads to H3S10ph increases
causing aberrant gene expression and cell death. Using both yeast overexpression models of C9orf72 and
human neuronal models the specific goals of this proposal are to: (1) characterize crosstalk between H3S10ph
and other histone modifications; (2) test the role of Aurora B Kinase in cell death; and (3) define the genomic
regions impacted by H3S10ph increases.
 Overall, this research plan will uncover novel epigenetic mechanisms at play in FTD while maintaining
our upward research trajectory and enriching the research environment for undergraduate students at Brooklyn
College. The long-term benefit of this research is to create a novel mechanistic framework that can lead to new,
alternative approaches in the treatment of FTD and other ADRDs.

## Key facts

- **NIH application ID:** 10359300
- **Project number:** 1R15NS125394-01
- **Recipient organization:** BROOKLYN COLLEGE
- **Principal Investigator:** Mariana Plazas Torrente
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,000
- **Award type:** 1
- **Project period:** 2022-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359300

## Citation

> US National Institutes of Health, RePORTER application 10359300, New Targets in C9orf72 FTD: Exploring Histone H3 S10 Phosphorylation (1R15NS125394-01). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/10359300. Licensed CC0.

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