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Identifier uch.biology.msc//2003samara
Title Μελέτη του ρόλου του pH στο νεκρωτικό θάνατο νευρώνων του νηματώδους Caenorhabditis elegans
Alternative Title The role of pH homeostasis in the necrotic cell death of C.elegans neurons
Creator Samara, Chrysanthi
Abstract Διατμηματικό, συνεργαζόμενα Τμήματα Βιολογίας και Ιατρικής. Numerous studies implicate necrotic cell death in many devastating human pathologies, such as stroke and neurodegenerative diseases. It has been shown that specific calpains and aspartyl proteases are involved in dismantling the cell during necrotic cell death inflicted by a variety of insults in C. elegans. However, the precise mechanism by which these enzymes become activated and subsequently wreck havoc, demolishing the cell, remains unknown. A genetic screen for either enhancers or suppressors of necrotic cell death, in sensitized genetic backgrounds, where neurodegeneration is attenuated by calpain or aspartyl protease deficiency, implicated genes encoding regulators of cytoplasmic and lysosomal pH. In particular, mutations in subunits of the vacuolar (V) H+ ATPase, a pump that acidifies intracellular organelles including lysosomes and regulates cellular pH at the expense of ATP, significantly attenuate necrotic cell death. We observed similar effects on necrosis by RNAi with several subunits of the V ATPase, and by treatment with agents known to inhibit this pump, such as ammonium chloride. To further elucidate the role of intracellular pH in necrosis, we monitored intracellular in specific degenerating neurons using pH-sensitive GFP variants (pHluorins). We found that neurodegeneration is followed by marked decrease in cellular pH, which is partly alleviated by mutations or treatments reducing the activity of V ATPase and ameliorating cell death. In a striking analogy, acidosis accompanies neurodegeneration following stroke in mammals. Our findings suggest necrotic cell death mechanisms are likely conserved and that intracellular and lysosomal pH is an important determinant of necrosis. Consistently, we observed that induced alkalization of endosomal compartments by weak bases, significantly suppresses necrotic cell death. We propose that intracellular acidic pH conditions, which develop during necrosis, activate or further enhance the activity of acidic aspartyl proteases and other lysosomal hydrolases, thus contributing to cell destruction.
Issue date 2003-11-01
Date available 2004-02-25
Collection   Faculty/Department--Faculty of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
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