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Genetic models of C9orf72: what is toxic?
Thomas G Moens1, Linda Partridge2, Adrian M Isaacs3
1Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
Abstract:
A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems. Additionally, models have now been created to attempt to study the effects of repetitive RNA and dipeptide proteins in isolation and thus determine their relevance to disease.
Insights
A hexanucleotide repeat expansion in C9orf72 causes ALS and FTD. Research suggests toxic gain of function from RNA and proteins, not just gene loss, drives neurodegeneration in these conditions.
Area of Science:
- Neuroscience
- Genetics
Background:
- C9orf72 hexanucleotide repeat expansion is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Disease pathogenesis is hypothesized to involve either loss of C9orf72 function or toxic gain of function through RNA or dipeptide repeat proteins.
Purpose of the Study:
- To investigate the role of C9orf72 gene function and toxic byproducts in neurodegeneration.
- To differentiate the contributions of C9orf72 loss-of-function versus gain-of-function mechanisms in disease models.
Main Methods:
- Utilized mouse knockout models to assess the impact of C9orf72 loss-of-function.
- Employed model systems to study the effects of hexanucleotide DNA overexpression.
- Developed models to examine the isolated effects of repetitive RNA and dipeptide proteins.
Main Results:
- C9orf72 loss-of-function alone appears insufficient to cause neurodegeneration in mouse models.
- Overexpression of hexanucleotide DNA demonstrated sufficiency in inducing disease phenotypes across various model systems.
- Ongoing research focuses on isolating the pathogenic roles of repetitive RNA and dipeptide proteins.
Conclusions:
- The findings challenge the sole sufficiency of C9orf72 loss-of-function in ALS and FTD pathogenesis.
- Toxic gain-of-function mechanisms mediated by repetitive elements are strongly implicated.
- Further research is crucial to elucidate the specific contributions of RNA and protein aggregates to disease.