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Formation of polyglutamine inclusions in non-CNS tissue
K Sathasivam1, C Hobbs, M Turmaine
1Medical and Molecular Genetics, GKT Medical and Dental School, King's College, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
Insights
Polyglutamine inclusions, a hallmark of Huntington's disease (HD), form in non-neuronal tissues, not just the brain. This finding aids in developing therapies for HD by allowing monitoring outside the central nervous system.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder.
- It is caused by CAG/polyglutamine repeat expansion in the HD gene.
- Previous studies generated transgenic mice modeling HD with expanded CAG repeats.
Purpose of the Study:
- To investigate the presence and progression of polyglutamine inclusions in non-neuronal tissues.
- To understand the cause of muscle atrophy in the HD mouse model.
- To explore the potential for monitoring therapeutic agents in non-CNS tissues.
Main Methods:
- Generated transgenic mice with expanded CAG repeats in the HD gene.
- Examined neuronal and non-neuronal tissues for polyglutamine inclusions.
- Analyzed skeletal muscle for inclusion formation and atrophy progression.
Main Results:
- Polyglutamine inclusions were found in various post-mitotic cells outside the central nervous system (CNS).
- Inclusion formation occurs in skeletal muscle, preceding severe muscle atrophy.
- These findings support a concentration-dependent aggregation model, not requiring brain-specific factors.
Conclusions:
- Polyglutamine inclusions are not confined to the brain in this HD model.
- Non-CNS inclusion formation offers a viable strategy for in vivo drug monitoring for Huntington's disease therapies.
- This approach bypasses the need for agents to cross the blood-brain barrier initially.
Abstract:
Huntington's disease (HD) is one of a class of inherited progressive neurodegenerative disorders that are caused by a CAG/polyglutamine repeat expansion. We have previously generated mice that are transgenic for exon 1 of the HD gene carrying highly expanded CAG repeats which develop a progressive movement disorder and weight loss with similarities to HD. Neuronal inclusions composed of the exon 1 protein and ubiquitin are present in specific brain regions prior to onset of the phenotype, which in turn occurs long before specific neurodegeneration can be detected. In this report we have extended the search for polyglutamine inclusions to non-neuronal tissues. Outside the central nervous system (CNS), inclusions were identified in a variety of post-mitotic cells. This is consistent with a concentration-dependent nucleation and aggregation model of inclusion formation and indicates that brain-specific factors are not necessary for this process. To possibly gain insights into the wasting that is observed in the human disease, we have conducted a detailed analysis of the timing and progression of inclusion formation in skeletal muscle and an investigation into the cause of the severe muscle atrophy that occurs in the mouse model. The formation of inclusions in non-CNS tissues will be particularly useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.