Opera Medica et Physiologica

neurodegeneration

Activity DEPendent Transposition (ADEPT) and the Aging Brain

Introduction 

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PDF icon OMP_2016_03_0034.pdf2.84 MB

Abstract

Neurons adapt to stimuli through activity dependent changes to their transcriptome, a process mediated by immediate-early gene networks.  Recent findings that transcriptional activation of neuronal immediate-early genes requires the formation of controlled DNA double-strand breaks (DSBs) has come as a surprise and has profound implications for neuronal function, especially in the aging brain.  Here we review recent literature surrounding the phenomena of activity-dependent DNA DSBs in neurons and how this process may be exploited by transposable elements (TEs) in both naïve and aging neurons.  We hypothesize the existence of Activity DEPendent Transposition (ADEPT), where neuronal excitation is able to induce genomic rearrangements through either de novo integration of TEs or by homology-directed recombination of TE-derived repetitive sequences.  Epigenetic drift may cause the magnitude of ADEPT to increase with age, leading to genome instability, which we suggest presages most, if not all, neurodegenerative diseases.

From Pathology to Physiology of Calcineurin Signalling in Astrocytes

Introduction

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PDF icon OMP_2016_02_0029.pdf1.07 MB

Abstract

Astrocytes perform fundamental housekeeping functions in the central nervous system and through bidirectional communication with neurons are thought to coordinate synaptic transmission and plasticity. They are also renowned actors in brain pathology. Reactive gliosis and neuroinflammation are featured by many (if not all) acute and chronic neurodegenerative pathologies including Alzheimer’s disease (AD). The Ca2+/calmodulin-activated phosphatase calcineurin (CaN) plays a central role in the pathology-related changes of astroglial cells mainly through activation of the inflammation-related transcription factors Nuclear Factor of Activated T-cells (NFAT) and Nuclear Factor kB (NF-kB). In this contribution we focus on the mechanistic aspects of CaN signalling in astrocytes. We analyze the astroglial Ca2+ signalling toolkit in the context of Ca2+ signals necessary for CaN activation and focus on the astroglial CaN signalling through its direct target, NFAT, as well as the intricate relationships between CaN and NF-kB activation pathways.The majority of data about CaN-mediated signalling in astrocytes point to the role for CaN in pathology-related conditions while very little is currently known about signalling and function of astroglial CaN in physiology.

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