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Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits
Jeannie Chew1, Tania F Gendron2, Mercedes Prudencio2
1Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Abstract:
The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.
Insights
A new mouse model replicates C9orf72 frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) by expressing a G4C2 repeat expansion. This model exhibits key neuropathological and behavioral hallmarks of the human disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The C9orf72 G4C2 repeat expansion is the primary genetic driver of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS).
- Current research into c9FTD/ALS is limited by the absence of animal models that accurately reflect the disease's neuropathological and clinical features.
Purpose of the Study:
- To develop and characterize a novel mouse model that recapitulates key neuropathological and clinical aspects of c9FTD/ALS.
- To provide a valuable tool for investigating disease mechanisms and testing therapeutic interventions for c9FTD/ALS.
Main Methods:
- Somatic brain transgenesis using adeno-associated virus (AAV) to express a (G4C2)66 repeat expansion throughout the central nervous system of mice.
- Histopathological analysis of mouse brains to identify RNA foci, dipeptide repeat protein inclusions (poly(Gly-Pro), poly(Gly-Ala), poly(Gly-Arg)), and TDP-43 pathology.
- Assessment of neurodegeneration, including cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and brain weight reduction.
- Behavioral testing to evaluate motor deficits and other abnormalities analogous to human c9FTD/ALS symptoms.
Main Results:
- The developed mouse model exhibited hallmark neuropathological features, including nuclear RNA foci, dipeptide repeat protein inclusions, and TDP-43 pathology.
- Significant neurodegeneration was observed, characterized by loss of cortical neurons and cerebellar Purkinje cells, astrogliosis, and reduced brain weight.
- Mice displayed behavioral deficits mirroring clinical symptoms in c9FTD/ALS patients, such as hyperactivity, anxiety, antisocial behavior, and motor impairments.
Conclusions:
- The (G4C2)66 mouse model effectively mimics both the neuropathological and clinical phenotypes of c9FTD/ALS.
- This model serves as a crucial preclinical tool for advancing the understanding and treatment of C9orf72-associated neurodegenerative diseases.
