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Schludi, Martin H.; Becker, Lore; Garrett, Lillian; Gendron, Tania F.; Zhou, Qihui; Schreiber, Franziska; Popper, Bastian; Dimou, Leda; Strom, Tim M.; Winkelmann, Juliane; Thaden, Anne von; Rentzsch, Kristin; May, Stephanie; Michaelsen, Meike; Schwenk, Benjamin M.; Tan, Jing; Schoser, Benedikt; Dieterich, Marianne; Petrucelli, Leonard; Hölter, Sabine M.; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabe de Angelis, Martin; Klopstock, Thomas; Arzberger, Thomas; Edbauer, Dieter (2017): Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. In: Acta Neuropathologica, Vol. 134, No. 2: pp. 241-254
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Abstract

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.