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Published on: March 5, 2012
Analysis of heat shock transcription factor for suppression of polyglutamine toxicity
M Rimoldi1, A Servadio, V Zimarino
1Dibit, San Raffaele Scientific Institute, Milano, Italy.
Abstract:
Individually over-expressed chaperones can interfere with cytotoxicity and aggregation of polyglutamine proteins in disease models. As chaperones cooperate, the analysis of suppression or reversal of polyglutamine pathology may require ways to up-regulate multiple chaperone coding genes. This condition might be achieved by exogenous expression of de-repressed forms of heat shock transcription factor 1 (HSF1), which mediates induction of several genes coding cytosolic and nuclear chaperones. Here we present the rationale behind this possible approach and the caveats, and employ a non-neuronal cell system to test whether Ataxin-1 aggregation can be modulated by de-repressed HSF1 mutants through augmented expression of chaperone coding genes. In our experiments, HSF1 mutants have induced heat shock protein 70 and Human DnaJ (HDJ)-1 to intermediate levels. Cells expressing such mutants also showed partial reduction of Ataxin-1 [31Q] aggregation. A consolidated positive outcome of these tests in cellular models would encourage experiments in transgenic mice and prospects for pharmacological modulation of HSF1 activity or delivery.
Insights
Modulating heat shock transcription factor 1 (HSF1) can up-regulate chaperones, partially reducing polyglutamine protein aggregation in cellular models. This suggests a potential therapeutic strategy for neurodegenerative diseases involving polyglutamine expansion.
Area of Science:
- Neurobiology
- Molecular Biology
- Genetics
Background:
- Chaperones play a role in preventing protein aggregation in neurodegenerative diseases.
- Upregulating multiple chaperone genes may be necessary to combat polyglutamine protein aggregation.
Purpose of the Study:
- To investigate if de-repressed heat shock transcription factor 1 (HSF1) mutants can modulate Ataxin-1 aggregation by increasing chaperone expression.
- To test the efficacy of HSF1 modulation in a non-neuronal cell system.
Main Methods:
- Exogenous expression of de-repressed HSF1 mutants in a non-neuronal cell system.
- Measuring the expression levels of heat shock protein 70 (HSP70) and Human DnaJ (HDJ)-1.
- Assessing the aggregation of Ataxin-1 [31Q] in cells expressing HSF1 mutants.
Main Results:
- HSF1 mutants successfully induced HSP70 and HDJ-1 to intermediate levels.
- Cells expressing HSF1 mutants exhibited a partial reduction in Ataxin-1 [31Q] aggregation.
- The study demonstrates a link between HSF1 activity, chaperone induction, and polyglutamine aggregation reduction.
Conclusions:
- De-repressed HSF1 mutants can enhance chaperone expression and partially reduce polyglutamine protein aggregation in cellular models.
- These findings support further investigation in animal models and potential pharmacological interventions targeting HSF1 for polyglutamine diseases.
