Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

Li, Chengyuan; Ma, Jiacheng; Zhao, Huifang; Blagg, Brian S. J.; Dobrowsky, Rick T.

doi:10.1042/20120047

Cited by 27 publications

(28 citation statements)

References 57 publications

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“…These data support that iHsp70 facilitates the proteasomal degradation of c-jun to attenuate demyelination (Fig. 2) (Li et al, 2012). Importantly, the necessity of iHsp70 in preventing the increase in c-jun expression and demyelination was validated using myelinated DRG explants prepared from Hsp70 KO mice.…”

Section: 0– Intracellular Hsp70supporting

confidence: 80%

“…Importantly, the efficacy of modulating chaperones is not limited to neurodegenerative diseases driven by the formation of protein aggregates. Hsp70 has also been shown to downregulate inflammatory signaling, decrease oxidative stress and improve mitochondrial function in DPN and other conditions whose etiology is not linked to the formation of protein aggregates (Ianaro et al, 2003; Jones et al, 2011; Li et al, 2012; Ma et al, 2015; Madden et al, 2008; Saibil, 2013; Zhang et al, 2012). However, an important aspect of Hsp70 biology that must be considered in moving forward in therapy development is how modulating the intra- versus extracellular pools of Hsp70 may affect disease progression.…”

Section: 0– Molecular Chaperonesmentioning

confidence: 99%

“…Other cultures were prepared for immunoblot analysis of c-jun and the effects of the treatments on c-jun and phospho-c-jun expression quantified (C–E). Modified with permission from Li et al, (2012), ASN Neuro published by Portland Press.…”

Section: Figmentioning

confidence: 99%

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Promoting Neuronal Tolerance of Diabetic Stress

Emery

Dobrowsky

2016

International Review of Neurobiology

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The etiology of diabetic peripheral neuropathy (DPN) involves an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have targeted proteins and pathways regarded as “diabetes specific” as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. In a complex, chronic neurodegenerative disease such as DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove sufficiently beneficial to pharmacologically enhance the activity of endogenous cytoprotective pathways to aid neuronal tolerance to and recovery from glucotoxic stress. In pursuing this paradigm shift, we have shown that modulating the activity and expression of molecular chaperones such as heat shock protein 70 (Hsp70) may provide translational potential for the effective medical management of insensate DPN. Considerable evidence supports that modulating Hsp70 has beneficial effects in improving inflammation, oxidative stress and glucose sensitivity. Given the emerging potential of modulating Hsp70 to manage DPN, the current review discusses efforts to characterize the cytoprotective effects of this protein and the benefits and limitations that may arise in drug development efforts that exploit its cytoprotective activity.

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Section: 0– Intracellular Hsp70supporting

confidence: 80%

Section: 0– Molecular Chaperonesmentioning

confidence: 99%

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Promoting Neuronal Tolerance of Diabetic Stress

Emery

Dobrowsky

2016

International Review of Neurobiology

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“…This divergence provides an excellent therapeutic window to promote neuroprotection in the absence of toxicity; weekly administration of KU-32 reversed psychosensory, electrophysiologic, bioenergetic, and morphologic indices of DPN in diabetic mice (Urban et al, 2010(Urban et al, , 2012. Mechanistically, KU-32 binds Hsp90 directly (Matts et al, 2011), but the drug's neuroprotective efficacy depends upon the downstream action of Hsp70 (Urban et al, 2010;Li et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein 70 Is Necessary to Improve Mitochondrial Bioenergetics and Reverse Diabetic Sensory Neuropathy following KU-32 Therapy

Farmer

Pan

et al. 2013

J Pharmacol Exp Ther

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Impaired neuronal mitochondrial bioenergetics contributes to the pathophysiologic progression of diabetic peripheral neuropathy (DPN) and may be a focal point for disease management. We have demonstrated that modulating heat shock protein (Hsp) 90 and Hsp70 with the small-molecule drug KU-32 ameliorates psychosensory, electrophysiologic, morphologic, and bioenergetic deficits of DPN in animal models of type 1 diabetes. The current study used mouse models of type 1 and type 2 diabetes to determine the relationship of changes in sensory neuron mitochondrial bioenergetics to the onset of and recovery from DPN. The onset of DPN showed a tight temporal correlation with a decrease in mitochondrial bioenergetics in a genetic model of type 2 diabetes.In contrast, sensory hypoalgesia developed 10 weeks before the occurrence of significant declines in sensory neuron mitochondrial bioenergetics in the type 1 model. KU-32 therapy improved mitochondrial bioenergetics in both the type 1 and type 2 models, and this tightly correlated with a decrease in DPN. Mechanistically, improved mitochondrial function following KU-32 therapy required Hsp70, since the drug was ineffective in diabetic Hsp70 knockout mice. Our data indicate that changes in mitochondrial bioenergetics may rapidly contribute to nerve dysfunction in type 2 diabetes, but not type 1 diabetes, and that modulating Hsp70 offers an effective approach toward correcting sensory neuron bioenergetic deficits and DPN in both type 1 and type 2 diabetes.

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“…1c) [33, 52, 58, 59], and its fluorinated biphenyl derivative, the novologue KU-596 (Fig. 1d) [60, 61•].…”

Section: Pharmacologic Targeting Of Hsp90—the Fit and The Form Begetsmentioning

confidence: 99%

Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy

Dobrowsky

2016

Curr Diab Rep

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The chaperome constitutes a broad family of molecular chaperones and co-chaperones that facilitate the folding, refolding, and degradation of the proteome. Heat shock protein 90 (Hsp90) promotes the folding of numerous oncoproteins to aid survival of malignant phenotypes, and small molecule inhibitors of the Hsp90 chaperone complex offer a viable approach to treat certain cancers. One therapeutic attribute of this approach is the selectivity of these molecules to target high affinity oncogenic Hsp90 complexes present in tumor cells, which are absent in nontransformed cells. This selectivity has given rise to the idea that disease may contribute to forming a stress chaperome that is functionally distinct in its ability to interact with small molecule Hsp90 modulators. Consistent with this premise, modulating Hsp90 improves clinically relevant endpoints of diabetic peripheral neuropathy but has little impact in nondiabetic nerve. The concept of targeting the “diabetic chaperome”to treat diabetes and its complications is discussed.

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Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

Cited by 27 publications

References 57 publications

Promoting Neuronal Tolerance of Diabetic Stress

Promoting Neuronal Tolerance of Diabetic Stress

Heat Shock Protein 70 Is Necessary to Improve Mitochondrial Bioenergetics and Reverse Diabetic Sensory Neuropathy following KU-32 Therapy

Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy

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