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Schludi, M.H.* ; Becker, L. ; Garrett, L. ; Gendron, T.F.* ; Zhou, Q.* ; Schreiber, F.* ; Popper, B.* ; Dimou, L.* ; Strom, T.M. ; Winkelmann, J. ; von Thaden, A.* ; Rentzsch, K.* ; May, S.* ; Michaelsen, M.* ; Schwenk, B.M.* ; Tan, J. ; Schoser, B.* ; Dieterich, M.* ; Petrucelli, L.* ; Hölter, S.M. ; Wurst, W. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Klopstock, T.* ; Arzberger, T.* ; Edbauer, D.*

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

Acta Neuropathol. 134, 241–254 (2017)
Publ. Version/Full Text 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
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Journal Acta Neuropathologica
Quellenangaben Volume: 134, Issue: 2, Pages: 241–254 Article Number: , Supplement: ,
Publisher Springer
Publishing Place New York
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)
Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
POF-Topic(s) 30201 - Metabolic Health
30204 - Cell Programming and Repair
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500692-001
G-500600-001
G-500500-001
G-500700-001
G-503200-001
PubMed ID 28409281
DOI 10.1007/s00401-017-1711-0
WOS ID WOS:000405315500006
Scopus ID 85017454628
Erfassungsdatum 2017-06-08
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