title: Modelling C9orf72 dipeptide repeat proteins of a physiologically relevant size.
abstract: C9orf72 expansions are the most common genetic cause of FTLD and MND identified to date. Although being intronic, the expansion is translated into five different dipeptide repeat proteins (DPRs) that accumulate within patients' neurons. Attempts have been made to model DPRs in cell and animals. However, the majority of these use DPRs repeat numbers much shorter than those observed in patients. To address this we have generated a selection of DPR expression constructs with repeat numbers in excess of 1000 repeats, matching what is seen in patients. Small and larger DPRs produce inclusions with similar morphology but different cellular effects. We demonstrate a length dependent effect using electrophysiology with a phenotype only occurring with the longest DPRs. These data highlight the importance of using physiologically relevant repeat numbers when modelling DPRs.
authors: Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
authors: Janis
authors: J
authors: Bennion Callister
authors: Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
authors: Sarah
authors: S
authors: Ryan
authors: Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
authors: Joan
authors: J
authors: Sim
authors: Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
authors: Sara
authors: S
authors: Rollinson
authors: Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
authors: Stuart M
authors: SM
authors: Pickering-Brown
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D004151:Dipeptides / Q000235:genetics* / Q000378:metabolism; D055724:Electrophysiological Phenomena; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology; D007438:Introns / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D066329:Protein Aggregates; D011506:Proteins