Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31266945.
- Also identified by DOI 10.1038/s41467-019-10956-w and PMC identifier 6606620.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>28</sub>) specifically in neurons. GFP-PR<sub>28</sub> 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<sub>28</sub> heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR<sub>28</sub> transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.
Medical subject headings
- Amyotrophic Lateral Sclerosis
- C9orf72 Protein
- Dipeptides
- Disease Models, Animal