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A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

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Cell Stress and Chaperones Aims and scope

An Erratum to this article was published on 19 November 2013

Abstract

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1G93A similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca2+ accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1G93A transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.

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Acknowledgments

This work was supported by the Canadian Institutes for Health Research (MOP-77743 to HDD); the Muscular Dystrophy Association (MDA93897 to HDD); and the National Institutes of Health (1R21NS066129-01 to RC and HDD). The authors thank Laura Cooper for technical assistance, Dr. Richard Voellmy for the HSF1inact plasmid, Dr. Heidi McBride for pOCT-eGFP/dsRed plasmids, Atsushi Miyawaki for the mitochondrial pericam plasmid, and Dr. Richard Youle for the photoactivatable (PA)-pOCT-eGFP plasmid. The data were included in the M.Sc. theses of JRCC and KJHSL.

Declarations

Z. Jaffer, R. Chen and A. Rubenstein were employees of NexGenix Pharmaceuticals.

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Author notes

  1. Miranda L. Tradewell

    Present address: Miranda Writes Medical Communication, Toronto, ON, Canada, M6R 2B1

  2. Zahara M. Jaffer

    Present address: House Research Institute, Los Angeles, CA, 90057, USA

  3. Ruihong Chen

    Present address: OncoSynergy, San Francisco, CA, 94158, USA

  4. Allan E. Rubenstein

    Present address: NYU Langone Medical Center, New York, NY, 10019, USA

Authors and Affiliations

  1. Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, 3801 University St, Montreal, QC, Canada, H3A 2B4

    Jieun R. C. Cha, Kyle J. H. St. Louis, Miranda L. Tradewell, Benoit J. Gentil, Sandra Minotti & Heather D. Durham

  2. NexGenix Pharmaceuticals Holdings, New York, NY, 10019, USA

    Zahara M. Jaffer, Ruihong Chen & Allan E. Rubenstein

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  1. Jieun R. C. Cha
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  2. Kyle J. H. St. Louis
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Correspondence to Heather D. Durham.

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Jieun R. C. Cha and Kyle J. H. St. Louis contributed equally to the manuscript.

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Cha, J.R.C., St. Louis, K.J.H., Tradewell, M.L. et al. A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo. Cell Stress and Chaperones 19, 421–435 (2014). https://doi.org/10.1007/s12192-013-0467-2

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