Related Experiment Videos
CREB-binding protein sequestration by expanded polyglutamine
A McCampbell1, J P Taylor, A A Taye
1Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3B11, Bethesda, MD 20892-1250, USA. mccampba@ninds.nih.gov
Abstract:
Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.
Insights
Spinal and bulbar muscular atrophy (SBMA) involves toxic protein aggregates. Researchers found CREB-binding protein (CBP) is sequestered in these aggregates, reducing its function and causing cell death.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by CAG repeat expansion, leading to polyglutamine tracts in proteins.
- Nuclear dysfunction is implicated in SBMA pathogenesis due to polyglutamine expansion disrupting critical nuclear factors or processes.
Purpose of the Study:
- To investigate the role of CREB-binding protein (CBP) in the nuclear inclusions characteristic of SBMA.
- To determine if CBP sequestration contributes to polyglutamine-mediated toxicity.
Main Methods:
- Utilized cell culture, transgenic mouse models, and patient tissues to examine CBP localization within nuclear inclusions.
- Assessed soluble CBP levels and CBP mRNA expression in cells with expanded polyglutamine.
- Investigated the effect of CBP over-expression on neuronal cell survival in a polyglutamine toxicity model.
Main Results:
- CREB-binding protein (CBP) was found to be incorporated into nuclear inclusions in SBMA models and patient tissues.
- CBP was also observed in nuclear inclusions in a cell culture model of spinocerebellar ataxia type 3.
- Soluble CBP levels decreased in cells with expanded polyglutamine, despite increased CBP mRNA, suggesting sequestration.
- Over-expression of CBP protected neuronal cells from polyglutamine-induced toxicity.
Conclusions:
- These findings support a CBP-sequestration model for polyglutamine expansion diseases like SBMA.
- CBP plays a critical role in mitigating polyglutamine toxicity, and its sequestration contributes to disease pathogenesis.