Heat shock protein 90 in neurodegenerative diseases

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.

Figure 1

Heat shock proteins are induced upon Hsp90 inhibition. (A) Schematic representation of HSF-1 regulation by Hsp90 and its activation by Hsp90 inhibitors. (B) Treatment of cells with heat shock or an Hsp90 inhibitor (Hsp90i) results in HSF-1 trimerization [10]. (C) Systemic administration of the purine-scaffold Hsp90 inhibitor PU-DZ8 to AD transgenic mice results in Hsp70 induction in the brain [29].

Figure 2

Chemical structures of several representative Hsp90 inhibitors. GM = ansamycin class; PU-DZ8 = purine-scaffold class; KU-32 = novobiocin class.

Figure 3

Hsp90 shelters aberrant neuronal proteins. (A) Aberrant neuronal proteins regulated by Hsp90. To tolerate the accumulation of dysregulated processes and to allow the development of the disease phenotype, the functional stability of these aberrant processes likely requires a "buffering" mechanism, such as offered by Hsp90. These aberrant neuronal proteins activities develop Hsp90-dependency and promote disease progression. (B) Pharmacologic Hsp90 inhibition results in inactivation or degradation of Hsp90-regulated proteins, mainly by a proteasomal pathway.