Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamineexpanded AR protein accumulates in the cell nucleus in a liganddependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.spinal and bulbar muscular atrophy ͉ geranylgeranylacetone ͉ androgen receptor ͉ heat-shock factor-1

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

“…The chaperone machinery has the potential to neutralize the toxicity caused by misfolded and aggregated proteins, making the activation of molecular chaperones an attractive therapeutic strategy [21,41]. Treatment of CMVMJD135 mice with 17-DMAG markedly improved motor performance, given by the results in the motor swimming, rotarod and beam balance tests, reduced the expression levels of human ataxin-3 at protein level and reduced the nuclear aggregate load in the pontine nuclei.…”

“…Potent Hsp90 inhibitors, such as 17-AAG or 17-DMAG, have been shown to reduce aggregate load and toxicity in cell, fly, nematode and mouse models of several neurodegenerative diseases, dependently on HSF-1 [15][16][17][18][19][20]. Concerning polyQ diseases, these two compounds have been shown to have beneficial effects only for SBMA [19][20][21]. Despite its high potency, 17-AAG showed poor solubility and stability and demonstrated moderate toxicity in several clinical trials [22].…”

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

“…Several studies indicate that chaperones are potent suppressors of neurodegeneration and are, therefore, promising therapeutic targets for protein conformational disorders (reviewed in Muchowski and Wacker 2005). For example, treating a polyglutamine disease model with an antiulcer drug, geranylgeranylacetone (GGA), which can induce the expression of different Hsps, could suppress the accumulation of pathogenic proteins and ameliorate the related phenotype (Katsuno et al 2005). In a rat model of Parkinson's disease, Hsp104 was found to be similarly efficient (Lo Bianco et al 2008).…”

Hsp70 expression and induction as a readout for detection of immune modulatory components in food

“…To enhance cellular fitness and stress resistance, several compounds of different origins have been tested for their capacity to induce or co-induce Hsp expression (Zou et al 1998;Morimoto and Santoro 1998;Soti and Csermely 2006). Beneficial effects of compound-induced stress protein expression on the outcome of experimental diseases such as cardiac dysfunction and neurodegenerative disease have been observed in many models (Katsuno et al 2005;Westerheide and Morimoto 2005;Vigh et al 1997;Brundel et al 2006). However, the outcome of boosting the stress response on Hsp-specific T-cell regulation has not been studied before.…”