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Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.

Acta Neuropathol. 134, 241–254 (2017)
Publishers Version Research data DOI PMC
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Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Als ; C9orf72 ; Ftd ; Ftld ; Mnd ; Mouse Model ; Neurodegeneration ; Neurological Disorder; Dipeptide-repeat Proteins; Frontotemporal Dementia; Hexanucleotide Repeat; Transgenic Mice; Startle Reflex; Rna Foci; Toxicity; Pathology; Als/ftd; Als
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