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Calcium homeostasis in aging neurons

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      Abstract

      The nervous system becomes increasingly vulnerable to insults and prone to dysfunction during aging. Age-related decline of neuronal function is manifested by the late onset of many neurodegenerative disorders, as well as by reduced signaling and processing capacity of individual neuron populations. Recent findings indicate that impairment of Ca 2+ homeostasis underlies the increased susceptibility of neurons to damage, associated with the aging process. However, the impact of aging on Ca 2+ homeostasis in neurons remains largely unknown. Here, we survey the molecular mechanisms that mediate neuronal Ca 2+ homeostasis and discuss the impact of aging on their efficacy. To address the question of how aging impinges on Ca 2+ homeostasis, we consider potential nodes through which mechanisms regulating Ca 2+ levels interface with molecular pathways known to influence the process of aging and senescent decline. Delineation of this crosstalk would facilitate the development of interventions aiming to fortify neurons against age-associated functional deterioration and death by augmenting Ca 2+ homeostasis.

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      A synaptic model of memory: long-term potentiation in the hippocampus.

      Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
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        Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.
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          Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.

          Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.
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            Author and article information

            Affiliations
            simpleInstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas Heraklion, Crete, Greece
            Author notes

            Edited by: Joy Alcedo, Wayne State University, USA

            Reviewed by: Joy Alcedo, Wayne State University, USA; QueeLim Ch’Ng, King’s College London, UK

            *Correspondence: Nektarios Tavernarakis, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas, Vassilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece. e-mail: tavernarakis@ 123456imbb.forth.gr

            This article was submitted to Frontiers in Genetics of Aging, a specialty of Frontiers in Genetics.

            Journal
            Front Genet
            Front Genet
            Front. Gene.
            Frontiers in Genetics
            Frontiers Research Foundation
            1664-8021
            02 October 2012
            2012
            : 3
            3462315
            23060904
            10.3389/fgene.2012.00200
            Copyright © Nikoletopoulou and Tavernarakis.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

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            Figures: 1, Tables: 2, Equations: 0, References: 261, Pages: 17, Words: 0
            Categories
            Genetics
            Review Article

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