17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration

Waza, Masahiro; Adachi, Hiroaki; Katsuno, Masahisa; Minamiyama, Makoto; Sang, Chen; Tanaka, Fumiaki; Inukai, Akira; Doyu, Manabu; Sobue, Gen

doi:10.1038/nm1298

Cited by 348 publications

(310 citation statements)

References 43 publications

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“…Hsp90 complexes have been shown to exist in two main forms; one is a proteasome-targeting form associated with Hsp70 and Hop, and the other is a mature stabilizing form with cdc37 and p23 with higher ATPase activity, indicating higher binding affinity for the Hsp90 inhibitors [32,33]. We therefore investigated the status of Hsp90 in pDCs in mice that developed SLE and compared it with that in ICR (control) mice.…”

Section: Hsp90 Multichaperone Complex In Pdcs In Mice That Developed Slementioning

confidence: 99%

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease, and disease activity is associated with serum IFN-α level. Plasmacytoid dendritic cells (pDCs) sense microbial as well as self-nucleic acids by TLRs 7 and 9 and produce a large amount of IFN-α. Here, we show that heat shock protein 90 (Hsp90) associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Inhibition of Hsp90 by various approaches including the use of Hsp90 inhibitor, a geldanamycin derivative, suppressed the Hsp90 association with TLR7/9, which resulted in inhibition of IFN-α production, leading to improvement of SLE symptoms in mice. Notably, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Furthermore, we demonstrated that serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Our data demonstrate that Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases.Keywords: Hsp90 r IFN-α r Plasmacytoid DC r SLE r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is characterized by the generation of autoantibodies specific for native double-stranded (ds) Correspondence: Prof. Yasuaki Tamura e-mail: ytamura3566@gmail.com DNA and nucleic acid/protein complexes [1]. A growing body of evidence suggests that IFN-α promotes lupus [2], since many patients have elevated serum IFN-α levels [3,4] and PBMCs from patients exhibit an IFN-α-induced gene expression signature that correlates with disease severity [5,6]. Recent findings in both human and mouse models suggest that TLR7 and TLR9 may play central roles in maintenance and progression of the disease by C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2028-2041 Innate immunity 2029 promoting elevation of IFN-α levels from plasmacytoid dendritic cells (pDCs) [7][8][9] and by activating B cells to produce autoantibodies [10,11]. pDCs sense microbial nucleic acids by TLR7 and TLR9 and produce a large amount of IFN-α. pDCs specifically express TLR7 and TLR9 within endolysosmes, and TLR7 and TLR9 sense single-stranded RNA and unmethylated CpG-rich DNA [12][13][14][15]. Importantly, microbial nucleic acids share a basic structure with host-derived nucleic acids. Indeed, TLR9 is able to respond to mammalian DNA if expressed on the cell surface [16]. TLR7 also responds to host-derived single-stranded RNA [7]. Therefore, nucleic acid-sensing TLR7/9 has to be tightly controlled to avoid autoimmune reaction. Nucleic acid sensing within endolysosomes is thought to be a safety mechanism for self-nucleic acid, because self-nucleic acids are rapidly degraded by DNase and RNase before reaching endolysosomes. Self-derived nuc...

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Section: Hsp90 Multichaperone Complex In Pdcs In Mice That Developed Slementioning

confidence: 99%

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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“…Given the similarity between tumor cells and leukocytes with respect to their amoeboid migration (18), HSP90 could also be involved in interstitial leukocyte migration; thus, targeting HSP90 could ameliorate inflammation-associated diseases. As has been reported, HSP90 is considered to be a promising druggable target for treating inflammatory and neurodegenerative diseases (19,20). Therefore, the development of novel HSP90 inhibitors is necessary for the HSP90-based therapy of inflammation-associated diseases, including MS.…”

mentioning

confidence: 93%

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Deng

Shao

et al. 2015

The Journal of Immunology

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Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz–enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B’s effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

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“…Consequently, the hallmarks of polyQ disorders are nuclear inclusions (NIs) containing aggregated mutant proteins in affected neurons (Di Figlia et al, 1997;Paulson et al, 1997;Skinner et al, 1997). Although toxicity of NIs per se can be debated, a number of studies suggest deregulation of cellular components involved in folding and/or degradation of proteins as a possible mechanism of disease pathogenesis (Warrick et al, 1999;Bence et al, 2001;Miller et al, 2005;Vacher et al, 2005;Waza et al, 2005). Protein misfolding is expected to induce cellular stress response, including the activation of the JNK/cJun/AP-1 signaling pathway (Sherman and Goldberg, 2001;Nishitoh et al, 2002;Merienne et al, 2003;Garcia et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Mérienne¹,

Friedman²,

Akimoto³

et al. 2007

Neurobiology of Disease

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We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.

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17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration

Cited by 348 publications

References 43 publications

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

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