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Small heat-shock proteins protect from heat-stroke-associated neurodegeneration

Abstract

Heat stroke is a life-threatening condition, characterized by catastrophic collapse of thermoregulation and extreme hyperthermia. In recent years, intensification of heat waves has caused a surge of heat-stroke fatalities. The mechanisms underlying heat-related pathology are poorly understood. Here we show that heat stroke triggers pervasive necrotic cell death and neurodegeneration in Caenorhabditis elegans. Preconditioning of animals at a mildly elevated temperature strongly protects from heat-induced necrosis. The heat-shock transcription factor HSF-1 and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. HSP-16.1 localizes to the Golgi, where it functions with the Ca2+- and Mn2+-transporting ATPase PMR-1 to maintain Ca2+ homeostasis under heat stroke. Preconditioning also suppresses cell death inflicted by diverse insults, and protects mammalian neurons from heat cytotoxicity. These findings reveal an evolutionarily conserved mechanism that defends against diverse necrotic stimuli, and may be relevant to heat stroke and other pathological conditions involving necrosis in humans.

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Figure 1: Heat preconditioning protects against extreme thermal stress through HSF-1 and HSP-16.1.
Figure 2: HSP-16. 1 localizes to the medial Golgi and functions together with PMR-1 to mediate the protective effect of preconditioning against heat stroke.
Figure 3: HSF-1 and HSP-16.1 mediate protection against necrosis inflicted by diverse insults upon preconditioning.
Figure 4: Preconditioning requires PMR-1 to alleviate heat-stroke-induced cytoplasmic Ca 2+ overload.
Figure 5: Heat preconditioning protects mammalian neurons against extreme thermal stress through crystallin αA and PMR1.
Figure 6: HSP-16.1 requires PMR-1 to suppress heat-stroke-induced necrosis and cytoplasmic Ca 2+ overload.

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Acknowledgements

We thank K. Georgila, K. Palikaras and E. Bessa for help with cell-death assays, A. Pasparaki for technical support with experiments and C. Olendrowitz for help with electron microscopy. We thank S. Eimer for providing the Golgi and endosomal reporter constructs and for support with the electron microscopy, N. Chronis for providing the pN1-GCaMP2.0 plasmid, G. Caldwell for the α-synuclein-expressing C. elegans strain and K. Palikaras for the skn-1 RNAi plasmid. We thank J. Vanoevelen and F. Wuytack for the antibody against PMR-1, S. Mitrovic for the antibody against mannosidase II, G. Sourvinos for lentiviral plasmids, and S. Gascon for the pLV plasmid. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources (NCRR) of the National Institutes of Health (NIH), and S. Mitani (National Bioresource Project) in Japan. We thank A. Fire for plasmid vectors. V.N. is supported by an European Molecular Biology Organization (EMBO) Long Term Fellowship. This work was funded by grants from the European Research Council (ERC) and the European Commission 7th Framework Programme.

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N.K., V.N. and N.T. designed and carried out experiments. N.K. and N.T. analysed data and wrote the manuscript.

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Correspondence to Nektarios Tavernarakis.

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Kourtis, N., Nikoletopoulou, V. & Tavernarakis, N. Small heat-shock proteins protect from heat-stroke-associated neurodegeneration. Nature 490, 213–218 (2012). https://doi.org/10.1038/nature11417

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