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Related Concept Videos

Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

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

Katelyn A Russell1,2, Amelia A Shahrabi1,2, Suleyman C Akerman3,4

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A new viral vector approach effectively models amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in mice by targeting the C9orf72 gene repeat expansion. This method reveals key spinal cord pathologies and mild motor deficits, offering insights into disease mechanisms.

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • The C9orf72 gene repeat expansion is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • Existing mouse models often fail to adequately represent the spinal cord pathology crucial to ALS/FTD pathogenesis.

Purpose of the Study:

  • To develop and validate a novel AAV-mediated gene delivery system for modeling C9orf72-associated ALS/FTD.
  • To investigate the combined effects of C9orf72 repeat expansion and gene loss-of-function on neurological function and pathology.

Main Methods:

  • Adeno-associated virus (AAV) encoding 149 repeats of (G4C2) was administered intrathecally in neonatal mice.
  • Mice with varying degrees of endogenous C9orf72 loss were utilized to study gain- and loss-of-function mechanisms.
  • Longitudinal analyses included motor function tests, behavioral observations, and detailed spinal cord pathological assessments.

Main Results:

  • Widespread central nervous system (CNS) expression was achieved, with significant spinal cord targeting.
  • Repeat expression correlated with progressive muscle weakness and subtle gait abnormalities.
  • Spinal motor regions showed dipeptide repeat protein accumulation, neuronal loss (reduced NeuN), glial activation, and phosphorylated TDP-43 inclusions.
  • Coordination deficits and hyperactivity were observed, with some phenotypes being genotype-dependent.

Conclusions:

  • CNS-wide expression of C9orf72 repeats, coupled with reduced C9orf72 levels, creates a valid and mild model of ALS/FTD.
  • This model effectively recapitulates key pathological features and functional deficits relevant to human disease.
  • The findings highlight the importance of spinal cord pathology in C9orf72-related neurodegeneration.