Heat shock protein 90 in neurodegenerative diseases

Wenjie Luo,Anna Rodina,Weilin Sun,Gabriela Chiosis,Tony Taldone

doi:10.1186/1750-1326-5-24

Abstract

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

Highlights

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation
Its benefits may come from induction of Hsp70 and other chaperones able of redirecting neuronal aggregate formation, and capable of protective potential against protein toxicity, proposing Hsp90 inhibition as a pharmacological intervention to therapeutically increase expression of molecular chaperone proteins to treat neurodegenerative diseases where aggregation is central to the pathogenesis (Fig. (1))
The usefulness of Hsp90 inhibitors as clinical agents in neurodegenerative diseases will depend on whether their effects occur at concentrations of drug that are not toxic and on whether the drugs can be administered chronically in such a fashion so as to safely achieve these concentrations in the brain

Summary

Introduction

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. Studies in a mouse model of HD suggested that in neurons, protection by Hsp70 against the toxic effects of misfolded htt protein occurred by mechanisms independent of the deposition of fibrillar aggregates, namely by binding monomeric and/or low molecular mass SDS-soluble oligomers that are likely off-pathway to fibril formation, but may be potentially pathogenic [14].

Results

Conclusion