CRISPR/Cas9 does not facilitate stable expression of long C9orf72 dipeptides in mice.

Neurobiol Aging

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. Electronic address:

Published: December 2019

AI Article Synopsis

  • * The study aimed to create transgenic mice with DPRs longer than 1000 repeats by using alternative codon sequences to minimize instability.
  • * Results showed that while the DPR inserts integrated into the mouse genome, they did not remain stable across generations, suggesting that using viral vectors post-birth might be a better strategy for delivering long repeats.

Article Abstract

A C9orf72 repeat expansion is the most common cause of both frontotemporal dementia and motor neuron disease. The expansion is translated to produce dipeptide repeat proteins (DPRs), which are toxic in vivo and in vitro. However, the mechanisms underlying DPR toxicity remain unclear. Mouse models which express DPRs at repeat lengths found in human disease are urgently required to investigate this. We aimed to generate transgenic mice expressing DPRs at repeat lengths of >1000 using alternative codon sequences, to reduce the repetitive nature of the insert. We found that although these inserts did integrate into the mouse genome, the alternative codon sequences did not protect from instability between generations. Our findings suggest that stable integration of long DPR sequences may not be possible. Administration of viral vectors after birth may be a more effective delivery method for long repeats.

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Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.09.010DOI Listing

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