RT Journal Article
T1 Viral delivery of C9ORF72 hexanucleotide repeat expansions in mice lead to repeat length dependent neuropathology and behavioral deficits
A1 Herranz Martín, Saúl
A1 Azzouz, Mimoun
AB Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) and recapitulate the relevant human pathology and disease-related behavioural phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated C9orf72 RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggest that RNA foci pathology is not a good predictor of C9orf72 RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of C9orf72 disease pathogenesis. These AAV-mediated models of C9orf72-associated ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches.
PB The Company of Biologists
SN 1754-8411
SN 1754-8403
YR 2017
FD 2017-07-01
LK https://hdl.handle.net/20.500.14352/95721
UL https://hdl.handle.net/20.500.14352/95721
LA eng
NO Akaaboune, M., Culican, S. M., Turney, S. G. and Lichtman, J. W. (1999). Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286, 503-507. https://doi.org/10.1126/science.286.5439.503
NO European Research Council
DS Docta Complutense
RD 11 abr 2025