The Induction Levels of Heat Shock Protein 70 Differentiate the Vulnerabilities to Mutant Huntingtin among Neuronal Subtypes

Abstract

The reason why vulnerabilities to mutant polyglutamine (polyQ) proteins are different among neuronal subtypes is mostly unknown. In this study, we compared the gene expression profiles of three types of primary neurons expressing huntingtin (htt) or ataxin-1. We found that heat shock protein 70 (hsp70), a well known chaperone molecule protecting neurons in the polyQ pathology, was dramatically upregulated only by mutant htt and selectively in the granule cells of the cerebellum. Granule cells, which are insensitive to degeneration in the human Huntington's disease (HD) pathology, lost their resistance by suppressing hsp70 with siRNA, whereas cortical neurons, affected in human HD, gained resistance by overexpressing hsp70. This indicates that induction levels of hsp70 are a critical factor for determining vulnerabilities to mutant htt among neuronal subtypes. CAT (chloramphenicol acetyltransferase) assays showed that CBF (CCAAT box binding factor, CCAAT/enhancer binding protein ) activated, but p53 repressed transcription of the hsp70 gene in granule cells. Basal and mutant htt-induced expression levels of p53 were remarkably lower in granule cells than in cortical neurons, suggesting that different magnitudes of p53 are linked to distinct induction levels of hsp70. Surprisingly, however, heat shock factor 1 was not activated in granule cells by mutant htt. Collectively, different levels of hsp70 among neuronal subtypes might be involved in selective neuronal death in the HD pathology.

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

“…Surprisingly, the HSR, the most general defense against protein misfolding in the cytosol, is not activated early by polyQ-expanded htt exonI or full-length htt in our models. The same finding has been reported in neurons affected in polyQ toxicity (Hay et al 2004;Tagawa et al 2007). Yet the expression of heat-shock proteins has been shown to provide effective protection against polyQ toxicity (Warrick et al 1999;Carmichael et al 2000;Muchowski et al 2000;Wyttenbach et al 2000Wyttenbach et al , 2002Bao et al 2002;Barral et al 2004;Muchowski and Wacker 2005;Vacher et al 2005).…”

“…The HSR is universally triggered by the presence of misfolded proteins in the cytosol. The fact that misfolded polyQ expansion proteins do not trigger a HSR in neurons (Hay et al 2004;Tagawa et al 2007), neuron-like PC12 cells, or, remarkably, even in our yeast model further suggests that the peculiar properties of these misfolded proteins are universal.…”

“…In addition, polyQ can entrap certain transcription factors Riley and Orr 2006), and might differentially affect particular transcriptional re-sponses, such as the HRR. We and others have found recently that the neurons most severely affected by polyQ expansions have the most reduced levels of heatshock proteins (Hay et al 2004;Tagawa et al 2007; M.L. Duennwald and S. Lindquist, in prep.).…”

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

“…netically defined crossing of transgenic lines. Numerous reports have noted up-regulation of particular chaperones that correlate with neuroprotection (48)(49)(50), but by taking a genetic approach we were able to demonstrate that HSF1 is required for maintaining viability during the clinical phase of prion infection. Indeed, boosting the HSR during prion disease may be an effective therapeutic strategy.…”

“…HSF1 KO mice (n ϭ 7) inoculated with 3.5logLD 50 RML IP succumbed to disease faster than HSF1 WT control mice (n ϭ 13) by 44 days (Fig. 2B and Table S1) (P Ͻ 0.0001, log rank test).…”