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.
Highlights
C9orf72 expansions are the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) identified to date and are found in approximately one out of every twelve patients diagnosed with these diseases [1,2,3]
The protein product of this gene is of unknown function, in silico analysis suggests it may be related to DENN ‘differentially expressed in normal and neoplastic cells’ GDP exchange factors (GEFs) proteins [4,5]. Patients with this expansion have a particular hippocampal and cerebellar pathology that is not seen in other types of FTLD and MND, which results from the unconventional translation of the expanded repeat on both strands producing 5 separate dipeptide repeat proteins (DPRs) of unknown significance [6,7,8]
Since the original identification of the hexanucleotide repeat expansion in C9orf72 as the cause of FTLD and ALS linked to chromosome 9 in 2011, there have been numerous reports of attempts to model this in various cell types and animal species
Summary
C9orf expansions are the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) identified to date and are found in approximately one out of every twelve patients diagnosed with these diseases [1,2,3]. The protein product of this gene is of unknown function, in silico analysis suggests it may be related to DENN ‘differentially expressed in normal and neoplastic cells’ GDP exchange factors (GEFs) proteins [4,5] Patients with this expansion have a particular hippocampal and cerebellar pathology that is not seen in other types of FTLD and MND, which results from the unconventional translation of the expanded repeat on both strands producing 5 separate dipeptide repeat proteins (DPRs) of unknown significance [6,7,8]. Several studies have reported that it is the DPRs not the RNA foci that are responsible for toxicity at least in Drosophila models and cell culture [15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
