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New intracellular calcium stores and apoptosis mechanisms in neurons

Final Activity Report Summary - CALCIUM_NEURONS (New intracellular calcium stores and apoptosis mechanisms in neurons)

Increases in the intracellular Ca2+ concentration represent a ubiquitous transduction mechanism involved in a diverse range of cellular processes from fertilisation to programmed cell death (apoptosis). Three intracellular organelles are thought to play a crucial role in apoptosis: the endoplasmatic reticulum (ER), the mitochondria and more recently the lysosomes. Conversely, the ER and the mitochondria are regarded as the main intracellular Ca2+ stores and/or sinks. We have recently uncovered that acidic lysosomal-related organelles acts as intracellular Ca2+ stores from which stimuli-induced NAADP can release Ca2+.

Our 5-year research project focused on 1) extending the universality of acidic lysosomal-like organelles as intracellular Ca2+ stores to hippocampal neurons, and 2) exploring the intriguing theory that lysosomal membrane permeability observed in apoptosis can be a result of disruption of the lysosomal Ca2+ homeostasis and Ca2+ dynamics between different intracellular stores.

During the first year of the project and thanks to the funding from a European Reintegration Grant and the collaboration with Dr. Churchill and Dr. Galione (University of Oxford), we set up different novel protocols and state-of-art techniques to achieve our objectives. Among the most relevant techniques, we can name Calcium Imaging, microinjection of caged compounds and subsequent activation by photolysis, synthesis of caged NAADP and [32P]NAADP, HPLC purification of nucleotides such as NADP, NADPH and NAADP and detection of cathepsin released to the cytosol. Our preliminary results show that NAADP delivered intracellularly but not exogenously can release intracellular calcium in hippocampal neurons. Further work in the next following 4 years of the project is needed to understand this novel signalling pathway and its implication in apoptosis of neurons from hippocampus.