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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The C9orf72 G4C2 hexanucleotide repeat expansion 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 this model for studying C9-ALS/FTD pathogenesis and therapeutic development.

Main Methods:

• Utilized a previously described AAV mouse model carrying 66 G4C2 repeats.
• Evaluated molecular pathology, including RNA foci, dipeptide repeat protein aggregation, and stress granule formation.
• Assessed neurodegeneration, neuronal loss, clinical deficits, and TAR DNA-binding protein (TDP-43) dysfunction.

Main Results:

• The AAV-(G4C2)66 model exhibited key ALS pathological markers like RNA foci, DPR protein aggregates, and p62-positive stress granules.
• The model showed marginal neurodegeneration with negligible neuronal loss and no significant clinical deficits.
• No significant evidence of TDP-43 dysfunction was observed in this rodent model.

Conclusions:

• This AAV-(G4C2)66 mouse model is valuable for studying G4C2 repeat-driven DPR pathology and its molecular consequences.
• The model is not suitable for investigating disease-associated TDP-43 dysfunction or clinical impairments in C9-ALS/FTD.
• Further development of comprehensive models is needed to fully replicate the multifaceted cellular and behavioral aspects of C9-ALS.