C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD.
To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will facilitate developing therapies targeting pathways that prevent neurodegeneration and increase survival.
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Yuanjing
Y
Liu
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Amrutha
A
Pattamatta
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Tao
T
Zu
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Tammy
T
Reid
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Olgert
O
Bardhi
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Diseases, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
David R
DR
Borchelt
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
Anthony T
AT
Yachnis
Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; Genetics Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: ranum@ufl.edu.
Laura P W
LP
Ranum
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D009154:Mutation / Q000235:genetics
D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors