# Oligodendroglial Dysfunction in C9orf72 ALS and FTD

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $597,360

## Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized clinically and pathologically by
progressive weakness and degeneration of motor neurons. A subset of patients can also have frontotemporal
dementia with cortex injury. Though the symptoms of ALS are due to neuron degeneration, extensive research
has shown that support cells in the CNS, including microglia, astrocytes, and recently oligodendrocytes,
contribute to motor neuron degeneration. Our lab and others have shown that oligodendrocytes degenerate in
ALS and that dysfunctional oligodendrocytes contribute to motor neuron degeneration, perhaps through failure
of metabolic support to neurons. Oligodendrocyte dysfunction has been found in sporadic ALS, but also familial
ALS associated with mutations in superoxide dismutase. Importantly, research from our laboratory has shown
that oligodendrocytes play a critical role in neurodegeneration in SOD1 mice, since removing mutant SOD1
specifically from oligodendrocyte precursor cells (OPCs) and oligodendrocytes significantly prolongs lifespan in
this mouse model of ALS. In the last several years, many research groups have focused on the recently
discovered hexanucleotide repeat expansions (HREs) in C9orf72, which is the most common cause of familial
ALS and also a common cause of frontotemporal dementia. These studies have determined that the
neurotoxicity is likely due to both RNA- and dipeptide repeats (DPR) protein-mediated events. The exact
mechanism by which these events produce toxicity is unknown, but published work by our laboratory and
others has demonstrated that nucleocytoplasmic transport and nuclear pore proteins are disrupted in neurons
expressing C9orf72HREs and restoration of this critical cell function leads to attenuation of neuronal toxicity.
To date, there has been only one study on the role of C9orf72HREs in oligodendrocytes. In this proposal, we
will thoroughly investigate the role of C9orf72HREs in OPCs and oligodendrocytes and their contribution to
cellular dysfunction and degeneration in cellular and mouse models. We hypothesize that oligodendrocytes
are dysfunctional in C9orf72 ALS and that alterations of nucleocytoplasmic transport lead to
oligodendrocyte injury and reduced capacity for OPC differentiation.
Specifically we propose to determine whether there is oligodendrocyte degeneration and OPC
proliferation in ALS patients, and animal models with C9orf72 HREs. Our preliminary studies suggest
C9orf72 is highly expressed in oligodendrocytes, which are dysfunctional in C9orf72 patients. We will then
determine whether OPCs fail to differentiate and/or oligodendrocytes degenerate in C9orf72 ALS due
to direct effect of repeat expansion on oligodendrocytes or an indirect effect from neuronal toxicity.
Using oligodendrocyte monocultures and co-cultures with neurons derived from C9orf72 iPS cells and C9BAC
mice, along with appropriate controls, we will evaluate OPC and oligodendrocyte proliferation, dif...

## Key facts

- **NIH application ID:** 10158335
- **Project number:** 5R01NS099320-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** BRETT M. MORRISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $597,360
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158335

## Citation

> US National Institutes of Health, RePORTER application 10158335, Oligodendroglial Dysfunction in C9orf72 ALS and FTD (5R01NS099320-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10158335. Licensed CC0.

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