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Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription
T Shimohata1, T Nakajima, M Yamada
1Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
Abstract:
At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.
Insights
Expanded polyglutamine (polyQ) stretches in neurodegenerative diseases bind to TAFII130, suppressing gene transcription. Restoring TAFII130 levels can reverse this suppression and cell death, revealing a key mechanism in neurodegeneration.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Inherited neurodegenerative diseases are linked to expanded CAG repeats forming polyglutamine (polyQ) stretches.
- The precise molecular mechanisms driving neurodegeneration due to these expanded polyQ stretches are not fully understood.
Purpose of the Study:
- To investigate the molecular interactions and functional consequences of expanded polyQ stretches in neurodegeneration.
- To identify the specific cellular targets and pathways affected by polyQ expansion.
Main Methods:
- Investigated the binding interactions between expanded polyQ stretches and cellular proteins.
- Assessed the impact of polyQ expansion on transcriptional activation, specifically CREB-dependent pathways.
- Utilized co-expression systems to evaluate rescue effects.
Main Results:
- Expanded polyQ stretches demonstrate a preferential binding affinity for TAFII130, a crucial coactivator for CREB-dependent transcription.
- This binding leads to a significant suppression of CREB-dependent transcriptional activity.
- Co-expression of TAFII130 successfully restored both the suppressed transcription and the polyQ-induced cell death.
Conclusions:
- The binding of expanded polyQ stretches to TAFII130 interferes with CREB-dependent transcription.
- This transcriptional interference is a key factor in the pathogenesis of polyQ-mediated neurodegenerative diseases.
- Targeting the TAFII130-polyQ interaction may offer therapeutic strategies for these conditions.