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IMBB researchers uncover a universal and potent protective mechanism against neuronal necrosis.

Sep 13, 2012

Research at the Institute of Molecular Biology and Biotechnology, published today in the premier international scientific journal Nature, reveals a novel molecular mechanism that strongly and generally defends against necrotic cell death triggered by extreme temperature and multiple other insults.

In recent years, intensification of heat waves because of the climate change has caused a surge of heat stroke fatalities throughout the globe (more than 70,000 deaths during the 2003 heat wave, in Europe alone). During heat stroke, core body temperature in excess of 40oC elicits widespread cell death and consequent multi-organ failure that is often fatal. The nervous system is particularly vulnerable and heat stroke survivors commonly suffer permanent neurological damage. Although heat-related pathologies such as heat stroke are estimated to soon become one of most serious causes of mortality, the cellular and molecular mechanisms responsible for the direct cytotoxicity of heat are not well-understood.

A complex interplay between acute physiological alterations, inflammatory and coagulation responses underlies the pathophysiology of heat stroke. The common denominator and trigger of these events is the direct cytotoxicity of heat. Despite the severity and the increasing health risks associated with heat-inflicted damage, the cellular and molecular mechanisms responsible for the cytotoxicity of heat are not well-understood. This is partly due to the lack of appropriate models, where the direct effects of heat on cell function and survival can be studied at the organismal level, away from secondary physiological and inflammatory responses.

To overcome these obstacles and to tackle the molecular basis of heat cytotoxicity, IMBB researchers Dr. Nikos Kourtis and Dr. Vassiliki Nikoletopoulou, headed by Prof. Nektarios Tavernarakis, have established a model of heat stroke in the simple nematode worm Caenorhabditis elegans. This model faithfully recapitulates cellular pathology following heat stroke in mammals, indicating its potential clinical relevance. The IMBB researchers utilized this model to obtain significant, new insights relevant to the mechanisms that mediate heat cytotoxicity. Exposure of nematodes to extreme temperature causes extensive necrotic cell death, simulating cases of heat stroke in humans. While searching for protective mechanisms against this type of death, they discovered that pre-emptive activation of the highly conserved heat shock response pathway had a strong protective effect against necrosis. This pathway converges on a specific subcellular organelle, the Golgi apparatus, to preserve its function as a calcium storage and homeostasis compartment, under conditions of extreme stress. It is the first time that this organelle is directly implicated in necrosis.

Importantly, IMBB researchers found that this strong protective mechanism both ubiquitous and universal. In addition to nematode, mammalian neurons are also shielded against necrotic death triggered by hyperthermia. Moreover, activation of the heat shock response generally and potently suppresses necrosis inflicted by diverse insults, unrelated to heat, such as hypoxia and excitotoxicity prevalent in stroke, and protein aggregation, implicated in neurodegenerative disorders, such as Parkinson's and Alzheimer's disease.

The novel findings reported by IMBB investigators reveal new players in the process of necrotic cell death and highlight the protective effect of an endogenous stress response pathway with the capacity to defend against heat cytotoxicity and multiple other necrotic insults. Such information could be effectively utilized towards identifying candidate common intervention targets, in an effort to battle the contemporary and increasingly prevalent heat stroke hazard, as well as other pathological conditions involving necrosis in humans.

For more information please contact:

Prof. Nektarios Tavernarakis, Research Director

Email: tavernarakis@imbb.forth.gr | Tel.: +30 2810391066

Relevant links: http://www.elegans.gr/ & http://www.nature.com/nature/index.html