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Huntington Disease l: Introduction

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Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...

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Updated: Jun 20, 2026

Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis

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Published on: July 16, 2021

Intrathecal (G₄C₂)₁₄₉ delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological

Katelyn A Russell^1,2, Amelia A Shahrabi^1,2, Suleyman C Akerman^3,4

¹Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Acta Neuropathologica Communications

|June 19, 2026

Summary

A new mouse model effectively mimics amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by using a viral vector to express C9ORF72 repeats in the central nervous system (CNS), revealing key disease mechanisms.

Keywords:

ALS ALS/FTD C9orf72 C9orf72 repeat expansions FTD Motor neuron disease Mouse models Neurodegenerative disease

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Area of Science:

Neuroscience
Genetics
Molecular Biology

Background:

C9ORF72 repeat expansions are the leading genetic cause of ALS and FTD.
Existing mouse models do not fully recapitulate spinal cord pathology relevant to these diseases.

Purpose of the Study:

To develop a more comprehensive mouse model for ALS and FTD by targeting the C9ORF72 gene.
To investigate both gain- and loss-of-function mechanisms contributing to disease pathogenesis.

Main Methods:

Adeno-associated virus (AAV) encoding (G4C2)149 repeats was administered intrathecally in neonatal mice.
Mice with varying degrees of endogenous C9orf72 loss were utilized.
Longitudinal analyses included motor function, behavior, and neuropathology.

Main Results:

Widespread CNS expression with significant spinal cord targeting was achieved.
Repeat expression led to progressive muscle weakness and subtle gait abnormalities.
Spinal motor regions showed dipeptide repeat protein accumulation, motor neuron loss, glial activation, and TDP-43 alterations.

Conclusions:

This AAV-based approach creates a coherent, mild mouse model of ALS/FTD.
The model effectively links C9ORF72 repeat expression, spinal pathology, and motor dysfunction.
It provides a valuable tool for studying ALS and FTD pathogenesis and for therapeutic development.