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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Launching Hsp70 neuroprotection a
Pedro Fernandez-Funez & Diego E Rincon-Limas
a
a
Departments of Neurology and Neuroscience; McKnight Brain Institute; Genetics Institute and Center for Translational Research on Neurodegenerative Diseases; University of Florida; Gainesville, FL USA Published online: 08 May 2014.
Click for updates To cite this article: Pedro Fernandez-Funez & Diego E Rincon-Limas (2014) Launching Hsp70 neuroprotection, Cell Cycle, 13:11, 1657-1658, DOI: 10.4161/cc.29148 To link to this article: http://dx.doi.org/10.4161/cc.29148
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Editorials: Cell Cycle Features
Editorials: Cell Cycle Features
Cell Cycle 13:11, 1657–1658; June 1, 2014; © 2014 Landes Bioscience
Launching Hsp70 neuroprotection Two drugs better than one Pedro Fernandez-Funez and Diego E Rincon-Limas
Downloaded by [Michigan State University] at 23:10 19 February 2015
Departments of Neurology and Neuroscience; McKnight Brain Institute; Genetics Institute and Center for Translational Research on Neurodegenerative Diseases; University of Florida; Gainesville, FL USA
A large number of neurodegenerative disorders are triggered by the aggregation of misfolded proteins called amyloids. The main pathogenic event in these proteinopathies is the accumulation of oligomers, soluble assemblies that can disrupt synaptic activity, alter intracellular signaling, and spread to neighboring cells. Thus, preventing the formation of oligomers is a common therapeutic strategy for many neurodegenerative disorders. A number of laboratories are focusing on developing specific anti-amyloid agents, but this deliberate approach may benefit only the most prevalent conditions, such as Alzheimer and Parkinson disease. Alternatively, it may be possible to target the conserved structure and pathobiology of amyloids with potentially widespread benefits. Interestingly, cells produce protein machines that prevent protein misfolding and aggregation and promote protein refolding: the molecular chaperones. The mighty Heat shock protein 70 (Hsp70) is the most abundant and efficient chaperone, binds a variety of substrates, and exerts numerous essential functions, from routine protein synthesis to stress response. Hence, Hsp70 is an ideal therapeutic target against the deleterious effects of amyloids. Unfortunately, Hsp70 is a poor pharmacologic target because its constitutive isoforms are highly expressed, it has high affinity for misfolded substrates, and it’s easily activated by abundant ATP. The key, though, is tapping into an abundant source of Hsp70 exclusively activated under cellular stress: the inducible Hsp70. Unfortunately, stress-inducing conditions are not appropriate therapeutic methods
for obvious reasons. In a recent paper, we efficiently induced Hsp70 by combining 2 compounds with different targets and pharmacologic mechanisms.1 A fascinating mechanism regulating the transcription of inducible Hsp70 offers an opportunity to highjack Hsp70 expression. The main transcriptional activator of inducible Hsp70 is heat shock factor 1 (HSF1), which under physiological conditions binds Hsp90, inhibiting its transcriptional activity (Fig. 1). Under stress, Hsp90 binds misfolded substrates, releasing HSF1, which induces the expression of several Heat shock proteins (HSPs). Here, the neurodegeneration field got an assist from cancer, because Hsp90 is a relevant target in cancer biology. Hsp90 allows certain tumors to stabilize otherwise lethal mutations in protein kinases, steroid hormone receptors, and transcription factors, all with oncogenic activity. Hsp90 inhibitors inactivate, destabilize, and degrade these oncogenic clients,2 limiting the survival of tumorous cells. The antibiotic geldanamycin, the first identified Hsp90 inhibitor, has shown some promise in cellular and animal tumor models but exhibits poor solubility and high toxicity. Several geldanamycin derivatives with improved solubility are now available but are still toxic due to the essential function of Hsp90. Although decades of research have led to a rational pharmacologic strategy to block the toxicity of amyloids, we still face serious obstacles for launching the protective HSP response. To optimize the pharmacological activation of Hsp70, we exploited a Drosophila model of prionopathies in which the
hamster prion protein (PrP) progressively misfolds and induces neurotoxicity.3 We showed previously that co-expression of Hsp70 rescued both PrP misfolding and neurotoxicity, suggesting that a fraction of Hsp70 directly binds PrP at the membrane, prevents its misfolding, and promotes its degradation by unknown mechanisms.3 These results led us to study the potential protective activity of pharmacologic activators of Hsp70. We first fed flies a water-soluble geldanamycin derivative, 17-DMAG, but high doses of 17-DMAG had no effect on PrP accumulation. Instead of increasing the 17-DMAG dose, which could lead to toxicity, we searched for other compounds known to activate Hsp70. We found an FDA-approved glucocorticoid with antiinflammatory activity, dexamethasone, which was described as an Hsp70 activator, among its many other activities. Dexamethasone is proposed to increase the affinity of HSF1 for the Hsp70 promoter, thus resulting in stronger transcriptional activity. However, dexamethasone alone had no effect on PrP levels. Remarkably, the combination of 17-DMAG and dexamethasone resulted in a significant reduction of the PrP steady-state levels that was accompanied by significant increases of inducible Hsp70 mRNA and protein (Fig. 1), but not constitutive Hsp70.1 This robust induction of Hsp70 reduced the levels of pathogenic PrP conformations and improved locomotor activity. Overall, we described a novel drug combination resulting in significant and synergistic induction of Hsp70 and reduction of PrP while avoiding the potential deleterious effects of higher doses of either drug.
Correspondence to: Pedro Fernandez-Funez; Email: [email protected]; Diego E Rincon-Limas; Email: [email protected] Submitted: 04/22/2014; Accepted: 04/23/2014; Published Online: 05/08/2014 http://dx.doi.org/10.4161/cc.29148 Comment on: Zhang Y, et al. PLoS One 2014; 9:e88522; PMID:24523910; http://dx.doi.org/10.1371/journal.pone.0088522
www.landesbioscience.com
Cell Cycle 1657
Downloaded by [Michigan State University] at 23:10 19 February 2015
Figure 1. Synergistic activation of Hsp70. Left: inducible Hsp70 is not normally expressed, because HSF1 is bound to Hsp90. However, cellular stressors can release HSF1 from Hsp90. Right: 17-DMAG releases HSF1 to bind and activate the iHsp70 promoter, while dexamethasone increases the transcriptional activity of HSF1. Each drug has little effect alone, but their combination results in a potent, synergistic activation of iHsp70.
Outlook Quite remarkably, Hsp90 is a common therapeutic target in rather diverse conditions such as cancer and neurodegeneration. However, Hsp90 inhibitors seek different cellular effects in these almost
1658
Hsp90 is intended to promote the expression of a protective downstream target: inducible Hsp70. Although neurodegenerative conditions can benefit from the development of safer and more effective Hsp90 inhibitors from the cancer field, these compounds alone may be of limited use due to their inherent cellular toxicity. Therefore, alternative therapeutic strategies may be based on the identification of additional drugs with small individual effects on Hsp70 induction. The combination of 2 or more such compounds could exhibit a synergistic Hsp70-inducing activity, leading to highly effective therapies with widespread clinical applications, including proteinopathies (Fig. 1). References
opposite conditions: one of unregulated cell proliferation, the other of progressive neuronal loss. Inhibition of Hsp90 eliminates the protective activity of Hsp90 over oncogenic mutations, thus restricting the growth and viability of cancerous cells. In brain proteinopathies, inhibition of
Cell Cycle
1. Zhang Y, et al. PLoS One 2014; 9:e88522; PMID:24523910; http://dx.doi.org/10.1371/journal. pone.0088522 2. Garcia-Carbonero R, et al. Lancet Oncol 2013; 14:e358-69; PMID:23896275; http://dx.doi. org/10.1016/S1470-2045(13)70169-4 3. Fernandez-Funez P, et al. PLoS Genet 2009; 5:e1000507; PMID:19503596; http://dx.doi. org/10.1371/journal.pgen.1000507
Volume 13 Issue 11
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Launching Hsp70 neuroprotection a
Pedro Fernandez-Funez & Diego E Rincon-Limas
a
a
Departments of Neurology and Neuroscience; McKnight Brain Institute; Genetics Institute and Center for Translational Research on Neurodegenerative Diseases; University of Florida; Gainesville, FL USA Published online: 08 May 2014.
Click for updates To cite this article: Pedro Fernandez-Funez & Diego E Rincon-Limas (2014) Launching Hsp70 neuroprotection, Cell Cycle, 13:11, 1657-1658, DOI: 10.4161/cc.29148 To link to this article: http://dx.doi.org/10.4161/cc.29148
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Editorials: Cell Cycle Features
Editorials: Cell Cycle Features
Cell Cycle 13:11, 1657–1658; June 1, 2014; © 2014 Landes Bioscience
Launching Hsp70 neuroprotection Two drugs better than one Pedro Fernandez-Funez and Diego E Rincon-Limas
Downloaded by [Michigan State University] at 23:10 19 February 2015
Departments of Neurology and Neuroscience; McKnight Brain Institute; Genetics Institute and Center for Translational Research on Neurodegenerative Diseases; University of Florida; Gainesville, FL USA
A large number of neurodegenerative disorders are triggered by the aggregation of misfolded proteins called amyloids. The main pathogenic event in these proteinopathies is the accumulation of oligomers, soluble assemblies that can disrupt synaptic activity, alter intracellular signaling, and spread to neighboring cells. Thus, preventing the formation of oligomers is a common therapeutic strategy for many neurodegenerative disorders. A number of laboratories are focusing on developing specific anti-amyloid agents, but this deliberate approach may benefit only the most prevalent conditions, such as Alzheimer and Parkinson disease. Alternatively, it may be possible to target the conserved structure and pathobiology of amyloids with potentially widespread benefits. Interestingly, cells produce protein machines that prevent protein misfolding and aggregation and promote protein refolding: the molecular chaperones. The mighty Heat shock protein 70 (Hsp70) is the most abundant and efficient chaperone, binds a variety of substrates, and exerts numerous essential functions, from routine protein synthesis to stress response. Hence, Hsp70 is an ideal therapeutic target against the deleterious effects of amyloids. Unfortunately, Hsp70 is a poor pharmacologic target because its constitutive isoforms are highly expressed, it has high affinity for misfolded substrates, and it’s easily activated by abundant ATP. The key, though, is tapping into an abundant source of Hsp70 exclusively activated under cellular stress: the inducible Hsp70. Unfortunately, stress-inducing conditions are not appropriate therapeutic methods
for obvious reasons. In a recent paper, we efficiently induced Hsp70 by combining 2 compounds with different targets and pharmacologic mechanisms.1 A fascinating mechanism regulating the transcription of inducible Hsp70 offers an opportunity to highjack Hsp70 expression. The main transcriptional activator of inducible Hsp70 is heat shock factor 1 (HSF1), which under physiological conditions binds Hsp90, inhibiting its transcriptional activity (Fig. 1). Under stress, Hsp90 binds misfolded substrates, releasing HSF1, which induces the expression of several Heat shock proteins (HSPs). Here, the neurodegeneration field got an assist from cancer, because Hsp90 is a relevant target in cancer biology. Hsp90 allows certain tumors to stabilize otherwise lethal mutations in protein kinases, steroid hormone receptors, and transcription factors, all with oncogenic activity. Hsp90 inhibitors inactivate, destabilize, and degrade these oncogenic clients,2 limiting the survival of tumorous cells. The antibiotic geldanamycin, the first identified Hsp90 inhibitor, has shown some promise in cellular and animal tumor models but exhibits poor solubility and high toxicity. Several geldanamycin derivatives with improved solubility are now available but are still toxic due to the essential function of Hsp90. Although decades of research have led to a rational pharmacologic strategy to block the toxicity of amyloids, we still face serious obstacles for launching the protective HSP response. To optimize the pharmacological activation of Hsp70, we exploited a Drosophila model of prionopathies in which the
hamster prion protein (PrP) progressively misfolds and induces neurotoxicity.3 We showed previously that co-expression of Hsp70 rescued both PrP misfolding and neurotoxicity, suggesting that a fraction of Hsp70 directly binds PrP at the membrane, prevents its misfolding, and promotes its degradation by unknown mechanisms.3 These results led us to study the potential protective activity of pharmacologic activators of Hsp70. We first fed flies a water-soluble geldanamycin derivative, 17-DMAG, but high doses of 17-DMAG had no effect on PrP accumulation. Instead of increasing the 17-DMAG dose, which could lead to toxicity, we searched for other compounds known to activate Hsp70. We found an FDA-approved glucocorticoid with antiinflammatory activity, dexamethasone, which was described as an Hsp70 activator, among its many other activities. Dexamethasone is proposed to increase the affinity of HSF1 for the Hsp70 promoter, thus resulting in stronger transcriptional activity. However, dexamethasone alone had no effect on PrP levels. Remarkably, the combination of 17-DMAG and dexamethasone resulted in a significant reduction of the PrP steady-state levels that was accompanied by significant increases of inducible Hsp70 mRNA and protein (Fig. 1), but not constitutive Hsp70.1 This robust induction of Hsp70 reduced the levels of pathogenic PrP conformations and improved locomotor activity. Overall, we described a novel drug combination resulting in significant and synergistic induction of Hsp70 and reduction of PrP while avoiding the potential deleterious effects of higher doses of either drug.
Correspondence to: Pedro Fernandez-Funez; Email: [email protected]; Diego E Rincon-Limas; Email: [email protected] Submitted: 04/22/2014; Accepted: 04/23/2014; Published Online: 05/08/2014 http://dx.doi.org/10.4161/cc.29148 Comment on: Zhang Y, et al. PLoS One 2014; 9:e88522; PMID:24523910; http://dx.doi.org/10.1371/journal.pone.0088522
www.landesbioscience.com
Cell Cycle 1657
Downloaded by [Michigan State University] at 23:10 19 February 2015
Figure 1. Synergistic activation of Hsp70. Left: inducible Hsp70 is not normally expressed, because HSF1 is bound to Hsp90. However, cellular stressors can release HSF1 from Hsp90. Right: 17-DMAG releases HSF1 to bind and activate the iHsp70 promoter, while dexamethasone increases the transcriptional activity of HSF1. Each drug has little effect alone, but their combination results in a potent, synergistic activation of iHsp70.
Outlook Quite remarkably, Hsp90 is a common therapeutic target in rather diverse conditions such as cancer and neurodegeneration. However, Hsp90 inhibitors seek different cellular effects in these almost
1658
Hsp90 is intended to promote the expression of a protective downstream target: inducible Hsp70. Although neurodegenerative conditions can benefit from the development of safer and more effective Hsp90 inhibitors from the cancer field, these compounds alone may be of limited use due to their inherent cellular toxicity. Therefore, alternative therapeutic strategies may be based on the identification of additional drugs with small individual effects on Hsp70 induction. The combination of 2 or more such compounds could exhibit a synergistic Hsp70-inducing activity, leading to highly effective therapies with widespread clinical applications, including proteinopathies (Fig. 1). References
opposite conditions: one of unregulated cell proliferation, the other of progressive neuronal loss. Inhibition of Hsp90 eliminates the protective activity of Hsp90 over oncogenic mutations, thus restricting the growth and viability of cancerous cells. In brain proteinopathies, inhibition of
Cell Cycle
1. Zhang Y, et al. PLoS One 2014; 9:e88522; PMID:24523910; http://dx.doi.org/10.1371/journal. pone.0088522 2. Garcia-Carbonero R, et al. Lancet Oncol 2013; 14:e358-69; PMID:23896275; http://dx.doi. org/10.1016/S1470-2045(13)70169-4 3. Fernandez-Funez P, et al. PLoS Genet 2009; 5:e1000507; PMID:19503596; http://dx.doi. org/10.1371/journal.pgen.1000507
Volume 13 Issue 11
