Nature Communications · 2019 · 107 citations · 45 references
Life SciencesGeneticsNeuroscienceMolecular NeurobiologyMolecular NeuroscienceNeurodegenerationAmyotrophic Lateral SclerosisMolecular Basis Of NeurodegenerationMolecular NeurogeneticsNeurodegenerative Disease GeneticsNeurodegenerative DiseasesNeurodegenerative DisordersAmyotrophic Lateral Sclerosis ModelsAmyotrophic Lateral Sclerosis PathologyC9orf72 Repeat ExpansionC9orf72-associated Frontotemporal DementiaDifferential Gene ExpressionNeurodegeneration PathogenesisTransgenic MiceTransgenic Mouse Models
Abstract A GGGGCC hexanucleotide repeat expansion in intron 1 of chromosome 9 open reading frame 72 ( C9ORF72 ) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to the neuropathological features of c9FTD/ALS. Among the five DPRs, arginine-rich poly-PR are reported to be the most toxic. Here, we generate a transgenic mouse line that expresses poly-PR (GFP-PR 28 ) specifically in neurons. GFP-PR 28 homozygous mice show decreased survival time, while the heterozygous mice show motor imbalance, decreased brain weight, loss of Purkinje cells and lower motor neurons, and inflammation in the cerebellum and spinal cord. Transcriptional analysis shows that in the cerebellum, GFP-PR 28 heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR 28 transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.
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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Alan E. Renton, Elisa Majounie, Adrian J. Waite et al. · Neuron · 2011 · 4.5K citations · Full text