TY - JOUR
T1 - Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72
AU - Zhu, Qiang
AU - Jiang, Jie
AU - Gendron, Tania F.
AU - McAlonis-Downes, Melissa
AU - Jiang, Lulin
AU - Taylor, Amy
AU - Diaz Garcia, Sandra
AU - Ghosh Dastidar, Somasish
AU - Rodriguez, Maria J.
AU - King, Patrick
AU - Zhang, Yongjie
AU - La Spada, Albert R.
AU - Xu, Huaxi
AU - Petrucelli, Leonard
AU - Ravits, John
AU - Da Cruz, Sandrine
AU - Lagier-Tourenne, Clotilde
AU - Cleveland, Don W.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.
AB - Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.
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U2 - 10.1038/s41593-020-0619-5
DO - 10.1038/s41593-020-0619-5
M3 - Article
C2 - 32284607
AN - SCOPUS:85083345273
SN - 1097-6256
VL - 23
SP - 615
EP - 624
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 5
ER -