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Updated: Aug 17, 2026
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
cAMP-response element-binding protein and heat-shock protein 70 additively suppress polyglutamine-mediated toxicity
Kanae Iijima-Ando1, Priscilla Wu, Eric A Drier
1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. iijmaka@cshl.edu
Abstract:
Gene-specific expansion of polyglutamine-encoding CAG repeats can cause neurodegenerative disorders, including Huntington's disease. It is believed that part of the pathological effect of the expanded protein is due to transcriptional dysregulation. Using Drosophila as a model, we show that cAMP-response element-binding protein (CREB) is involved in expanded polyglutamine-induced toxicity. A mutation in the Drosophila homolog of CREB, dCREB2, enhances lethality due to polyglutamine peptides (polyQ), and an additional copy of dCREB2 partially rescues this lethality. Neuronal expression of expanded polyQ attenuates in vivo CRE-mediated transcription of a reporter gene. As reported previously, overexpression of heat-shock protein 70 (Hsp70) rescues polyglutamine-dependent lethality. However, it does not rescue CREB-mediated transcription. The protective effects of CREB and heat-shock protein 70 against polyQ are additive, suggesting that targeting multiple pathways may be effective for treatment of polyglutamine diseases.
Insights
Cyclic AMP-response element-binding protein (CREB) plays a role in polyglutamine toxicity, a hallmark of neurodegenerative diseases. Targeting CREB and heat-shock protein 70 may offer new therapeutic avenues for these conditions.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Polyglutamine (polyQ) diseases, such as Huntington's disease, are linked to CAG repeat expansions.
- Transcriptional dysregulation is a proposed mechanism underlying polyQ-induced neurotoxicity.
- The role of specific transcription factors in polyQ pathogenesis remains to be fully elucidated.
Purpose of the Study:
- To investigate the involvement of Cyclic AMP-response element-binding protein (CREB) in polyglutamine toxicity.
- To explore the interaction between CREB and heat-shock protein 70 (Hsp70) in mitigating polyQ-induced neurodegeneration.
Main Methods:
- Utilized Drosophila melanogaster as a model organism to study polyglutamine toxicity.
- Assessed the impact of mutations and gene copy number variations in the Drosophila CREB homolog (dCREB2) on polyQ-induced lethality.
- Measured CRE-mediated transcription using a reporter gene assay in neurons expressing expanded polyglutamine peptides.
Main Results:
- A mutation in dCREB2 exacerbated polyglutamine-induced lethality, while an extra copy of dCREB2 partially rescued it.
- Neuronal expression of expanded polyglutamine attenuated in vivo CRE-mediated transcription.
- Overexpression of Hsp70 rescued polyglutamine lethality but did not restore CREB-mediated transcription.
Conclusions:
- CREB is implicated in the toxicity associated with expanded polyglutamine peptides.
- The protective mechanisms of CREB and Hsp70 against polyglutamine toxicity operate through distinct pathways.
- Combined therapeutic strategies targeting both CREB and Hsp70 pathways may be beneficial for treating polyglutamine diseases.
