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CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation
C Gaspar1, M Jannatipour, P Dion
1Centre for Research in Neurosciences, McGill University, Montreal General Hospital, Québec, Canada.
Abstract:
Machado-Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG). The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.
Insights
Expanded CAG repeats in Machado-Joseph disease may produce toxic polyalanine proteins. These alanine polymers form intranuclear inclusions, contributing to nuclear toxicity and potentially other CAG repeat disorders.
Area of Science:
- Neurogenetics
- Molecular Biology
- Cellular Pathology
Background:
- Machado-Joseph disease (MJD) is linked to expanded CAG repeats (exp-CAG), leading to intranuclear inclusions (INIs) and a nuclear toxicity model.
- Oculopharyngeal muscular dystrophy shares INIs and is caused by expanded alanine-encoding GCG repeats.
Purpose of the Study:
- To investigate if transcriptional or translational frameshifts in expanded CAG tracts produce polyalanine mutant proteins.
- To determine if these polyalanine polymers form INIs and contribute to nuclear toxicity in MJD and other CAG repeat disorders.
Main Methods:
- Analysis of lymphoblast cells from MJD patients.
- Examination of pontine neurons from MJD brains.
- In vitro cell culture models of MJD.
Main Results:
- Evidence supporting the production and accumulation of polyalanine-containing mutant proteins in MJD models.
- Demonstration that these alanine polymers form INIs.
- Confirmation that alanine polymers alone exhibit cellular toxicity.
Conclusions:
- Frameshifts within expanded CAG tracts can generate toxic polyalanine proteins, forming INIs and causing nuclear toxicity.
- This pathogenic mechanism is likely relevant to Machado-Joseph disease and other CAG repeat expansion disorders.