# Characterization of TASK-1 Modulation of Dipeptide Repeat Protein-Mediated Toxicity in iPSC-derived C9ORF72 Patient Neurons.

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $460,625

## Abstract

Frontotemporal dementia (FTD) is the most common form of early-onset dementia. Loss of neurons in the
frontal and temporal lobes in the brain leads to progressive behavioral changes and language impairments in
people affected by the disease. Most of the familial cases can be explained by a hexanucleotide (GGGGCC)
repeat expansion in C9ORF72, a common feature shared between FTD and another degenerative disease,
amyotrophic lateral sclerosis (ALS). Brain tissues from affected individuals show characteristic nuclear RNA
foci containing the expanded repeat RNAs, as well as neuronal inclusions containing dipeptide repeat (DPR)
proteins resulting from the translation of both sense and antisense repeat RNAs in all reading frames. Although
reduced C9ORF72 protein function may contribute to disease, the more likely drivers of disease are
mechanisms related to a gain of toxic function. Currently, intense efforts are being made to identify disease
mechanisms amenable for the development of therapeutic strategies. The overall objective of this proposal is
to evaluate the modulation of endogenous DPR protein levels within an appropriate physiological context by
the potassium channel TASK1. Our hypothesis is that by decreasing DPR protein levels in human neurons it
may be possible to restore a healthy control phenotype and delay aspects of disease pathogenesis and
neurodegeneration. Our studies also aim to identify the mechanisms leading to TASK1-mediated clearance of
DPR proteins in patient neurons, an aspect not yet understood. Altogether, our studies seek to reveal new
therapeutic opportunities to treat C9ORF72-related FTD/ALS and possibly other neurodegenerative diseases
associated with DPR proteins.

## Key facts

- **NIH application ID:** 10108444
- **Project number:** 1R21NS119952-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Sandra Almeida
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,625
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108444

## Citation

> US National Institutes of Health, RePORTER application 10108444, Characterization of TASK-1 Modulation of Dipeptide Repeat Protein-Mediated Toxicity in iPSC-derived C9ORF72 Patient Neurons. (1R21NS119952-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10108444. Licensed CC0.

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