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Modelling C9orf72 dipeptide repeat proteins of a physiologically relevant size.
Janis Bennion Callister1, Sarah Ryan1, Joan Sim1
1Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
Human Molecular Genetics
|November 1, 2016
Summary
Genetic expansions in C9orf72 cause frontotemporal dementia and motor neuron disease. This study generated models with long repeat numbers, revealing length-dependent cellular effects crucial for accurate disease modeling.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- C9orf72 expansions are the leading genetic cause of frontotemporal dementia (FTLD) and motor neuron disease (MND).
- These intronic expansions produce dipeptide repeat proteins (DPRs) that aggregate in neurons.
- Existing cellular and animal models often use DPR repeat lengths shorter than those found in patients.
Purpose of the Study:
- To generate and characterize DPR expression constructs with physiologically relevant repeat numbers (>1000 repeats).
- To investigate the impact of DPR repeat length on cellular phenotypes and neuronal function.
Main Methods:
- Generation of DPR expression constructs with extended repeat numbers.
- Analysis of DPR inclusion morphology.
- Electrophysiological recordings to assess cellular effects.
Main Results:
- Both short and long DPRs formed inclusions with similar morphology.
- A length-dependent cellular phenotype was observed, with electrophysiological abnormalities only present with the longest DPRs.
- These findings underscore the importance of using patient-relevant repeat lengths in disease models.
Conclusions:
- Modeling C9orf72-associated disorders requires DPRs with repeat numbers exceeding 1000.
- DPR length significantly influences cellular dysfunction, impacting disease modeling accuracy.
- This study provides crucial insights for developing more relevant preclinical models of FTLD and MND.
