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A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.

Emily G Thompson1,2, Olivia Spead1,2, S Can Akerman1,2

  • 1Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

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Summary

The AAV-(G4C2)66 mouse model shows key C9-ALS/FTD molecular markers but lacks neurodegeneration and motor deficits. This model is useful for studying repeat-driven pathology, not disease progression.

Keywords:
Amyotrophic Lateral SclerosisC9orf72 repeat expansionDipeptide RepeatsGFAPNfLp62

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • The G4C2 hexanucleotide repeat expansion in C9ORF72 is a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • Developing accurate mouse models for C9-ALS/FTD is challenging due to complex genetic factors, molecular mechanisms, and species differences.

Purpose of the Study:

  • To investigate the cellular pathophysiology and behavioral outcomes in an AAV mouse model expressing 66 G4C2 repeats.
  • To assess the suitability of the AAV-(G4C2)66 model for studying C9-ALS/FTD pathogenesis and therapeutic development.

Main Methods:

  • Utilized an adeno-associated virus (AAV) vector to deliver 66 G4C2 repeats into a mouse model.
  • Assessed molecular pathology (RNA foci, DPR aggregation, stress granules, gliosis) and neuronal loss, motor function, and TDP-43 integrity.

Main Results:

  • The AAV-(G4C2)66 model exhibited molecular hallmarks of C9-ALS/FTD, including RNA foci, dipeptide repeat (DPR) protein aggregation, and stress granule formation.
  • Despite molecular pathology, the model showed negligible neuronal loss, no motor deficits, and unimpaired TDP-43 function.
  • The model is pharmacologically tractable for studying DPR pathology mechanisms but not neurodegeneration or motor deficits.

Conclusions:

  • The AAV-(G4C2)66 model is valuable for dissecting molecular aspects of G4C2 repeat-driven DPR pathology.
  • This model is not suitable for studying neurodegeneration, TDP-43 dysfunction, or motor impairments in C9-ALS/FTD.
  • More comprehensive models are needed to fully replicate the multifaceted cellular and behavioral aspects of C9-ALS/FTD.