Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

UMMS Affiliation

Department of Neurology; Department of Pediatrics, Division of Pulmonary and Allergy; Horae Gene Therapy Center



Document Type



Neurology | Neuroscience and Neurobiology


A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

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Citation: Neuron. 2015 Dec 2;88(5):902-9. doi: 10.1016/j.neuron.2015.11.018. Link to article on publisher's site


Full author list omitted for brevity. For full list of authors see article.

Related Resources

Link to Article in PubMed


Amyotrophic lateral sclerosis (ALS), C9ORF72, RAN translation, RNA foci, frontotemporal dementia (FTD), microRNA, neurodegeneration, repeat expansions, transgenic mice

PubMed ID