# Characterization of the involvement of the cerebellum in animal models of C9orf72 ALS/FTD

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2020 · $419,375

## Abstract

Project Summary:
 Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss
of motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD) is early-onset dementia caused
by degeneration of the frontal and temporal lobes with cognitive deficits and behavioral and language
abnormalities. FTD shares pathophysiological features with ALS. A hexanucleotide repeat expansion in an
intron of C9orf72 is the most frequently reported genetic cause of both diseases. Most of the
pathophysiological studies of C9orf72 ALS/FTD and other types of ALS so far have been focused on upper
and lower motor neurons. Recently, several functional studies have detected lower gray matter volume in the
cerebellum in pre-symptomatic C9orf72 repeat expansion carriers, and anatomical evidence in C9orf72
disease mouse models have demonstrated cerebellar degeneration. Furthermore, pathology reports using
postmortem or patient cells have demonstrated inclusions, RNA foci, dipeptide repeat proteins, and decreased
C9orf72 mRNA and protein levels in the cerebellum, especially Purkinje cells, implicating cerebellar
dysfunction in the pathogenesis of C9orf72 ALS/FTD. However, there are very few studies in animal disease
models focusing on the cerebellum. Our strong preliminary data on C9orf72 knockout mice has revealed motor
deficits and altered Purkinje cell activity. The functional significance of the cerebellum in the C9orf72 ALS/FTD
pathogenesis is not known, let alone the detailed mechanisms. These unknowns hamper efforts to understand
the pathophysiology of C9orf72 ALS/FTD and to develop effective therapies for patients. The overall goal of
our research is to use transgenic mice to study the pathophysiology of C9orf72 ALS/FTD. The specific goal of
this application is to characterize mouse models of C9orf72 ALS/FTD to determine the role of cerebellum in
the pathogenesis of ALS and FTD. We hypothesize that at the presymptomatic stage, the C9orf72 mutant
mice have motor deficits in coordination and balance, anatomical and functional deficits in the cerebellum,
especially in the Purkinje cells due to the loss of function of C9orf72 protein and changes in the ion channels.
We plan to test our hypothesis with the following Specific Aims: (1) we will examine C9orf72 mutant mice in
the behavioral test battery, (2) we will characterize neuronal morphology, passive membrane properties, and
intrinsic excitabilities of Purkinje cells, and (3) we will perform acutely dissociated Purkinje cell recording and
Western blot analysis to determine ion channels involved in the altered firing of Purkinje cells. The successful
completion of the Aims will expand the current knowledge concerning the involvement of the cerebellum in
C9orf72-mediated ALS/FTD. This should significantly increase our understanding of the pathophysiology of
C9orf72 ALS/FTD and contribute to the pathophysiological studies of other genetic ALS. Furthermore, the
outcome o...

## Key facts

- **NIH application ID:** 10041549
- **Project number:** 1R21NS118397-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** YUQING LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,375
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041549

## Citation

> US National Institutes of Health, RePORTER application 10041549, Characterization of the involvement of the cerebellum in animal models of C9orf72 ALS/FTD (1R21NS118397-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10041549. Licensed CC0.

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