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SIRT1 Promotes Neuronal Fortification in Neurodegenerative Diseases through Attenuation of Pathological Hallmarks and Enhancement of Cellular Lifespan.
Mishra, P, Mittal, AK, Kalonia, H, Madan, S, Ghosh, S, Sinha, JK, Rajput, SK
Current neuropharmacology. 2021;(7):1019-1037
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Abstract
Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.
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Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.
Gudenschwager, C, Chavez, I, Cardenas, C, Gonzalez-Billault, C
Oxidative medicine and cellular longevity. 2021;:5586052
Abstract
Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer's, Parkinson's, and Huntington's disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the "aged" context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.
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The role of Bcl-2 proteins in modulating neuronal Ca2+ signaling in health and in Alzheimer's disease.
Callens, M, Kraskovskaya, N, Derevtsova, K, Annaert, W, Bultynck, G, Bezprozvanny, I, Vervliet, T
Biochimica et biophysica acta. Molecular cell research. 2021;(6):118997
Abstract
The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling intracellular Ca2+ signaling, a critical process for the function of most cell types, including neurons. Several anti- and pro-apoptotic Bcl-2 family members are expressed in neurons and impact neuronal function. Importantly, expression levels of neuronal Bcl-2 proteins are affected by age. In this review, we focus on the emerging roles of Bcl-2 proteins in neuronal cells. Specifically, we discuss how their dysregulation contributes to the onset, development, and progression of neurodegeneration in the context of Alzheimer's disease (AD). Aberrant Ca2+ signaling plays an important role in the pathogenesis of AD, and we propose that dysregulation of the Bcl-2-Ca2+ signaling axis may contribute to the progression of AD and that herein, Bcl-2 may constitute a potential therapeutic target for the treatment of AD.
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Astroglial Isopotentiality and Calcium-Associated Biomagnetic Field Effects on Cortical Neuronal Coupling.
Martinez-Banaclocha, M
Cells. 2020;(2)
Abstract
Synaptic neurotransmission is necessary but does not sufficiently explain superior cognitive faculties. Growing evidence has shown that neuron-astroglial chemical crosstalk plays a critical role in the processing of information, computation, and memory. In addition to chemical and electrical communication among neurons and between neurons and astrocytes, other nonsynaptic mechanisms called ephaptic interactions can contribute to the neuronal synchronization from different brain regions involved in the processing of information. New research on brain astrocytes has clearly shown that the membrane potential of these cells remains very stable among neighboring and distant astrocytes due to the marked bioelectric coupling between them through gap junctions. This finding raises the possibility that the neocortical astroglial network exerts a guiding template modulating the excitability and synchronization of trillions of neurons by astroglial Ca2+-associated bioelectromagnetic interactions. We propose that bioelectric and biomagnetic fields of the astroglial network equalize extracellular local field potentials (LFPs) and associated local magnetic field potentials (LMFPs) in the cortical layers of the brain areas involved in the processing of information, contributing to the adequate and coherent integration of external and internal signals. This article reviews the current knowledge of ephaptic interactions in the cerebral cortex and proposes that the isopotentiality of cortical astrocytes is a prerequisite for the maintenance of the bioelectromagnetic crosstalk between neurons and astrocytes in the neocortex.
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SK2 channel regulation of neuronal excitability, synaptic transmission, and brain rhythmic activity in health and diseases.
Sun, J, Liu, Y, Baudry, M, Bi, X
Biochimica et biophysica acta. Molecular cell research. 2020;(12):118834
Abstract
Small conductance calcium-activated potassium channels (SKs) are solely activated by intracellular Ca2+ and their activation leads to potassium efflux, thereby repolarizing/hyperpolarizing membrane potential. Thus, these channels play a critical role in synaptic transmission, and consequently in information transmission along the neuronal circuits expressing them. SKs are widely but not homogeneously distributed in the central nervous system (CNS). Activation of SKs requires submicromolar cytoplasmic Ca2+ concentrations, which are reached following either Ca2+ release from intracellular Ca2+ stores or influx through Ca2+ permeable membrane channels. Both Ca2+ sensitivity and synaptic levels of SKs are regulated by protein kinases and phosphatases, and degradation pathways. SKs in turn control the activity of multiple Ca2+ channels. They are therefore critically involved in coordinating diverse Ca2+ signaling pathways and controlling Ca2+ signal amplitude and duration. This review highlights recent advances in our understanding of the regulation of SK2 channels and of their roles in normal brain functions, including synaptic plasticity, learning and memory, and rhythmic activities. It will also discuss how alterations in their expression and regulation might contribute to various brain disorders such as Angelman Syndrome, Alzheimer's disease and Parkinson's disease.
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Lessons on Differential Neuronal-Death-Vulnerability from Familial Cases of Parkinson's and Alzheimer's Diseases.
Franco, R, Navarro, G, Martínez-Pinilla, E
International journal of molecular sciences. 2019;(13)
Abstract
The main risk of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common neurodegenerative pathologies, is aging. In contrast to sporadic cases, whose symptoms appear at >60 years of age, familial PD or familial AD affects younger individuals. Finding early biological markers of these diseases as well as efficacious treatments for both symptom relief and delaying disease progression are of paramount relevance. Familial early-onset PD/AD are due to genetic factors, sometimes a single mutation in a given gene. Both diseases have neuronal loss and abnormal accumulations of specific proteins in common, but in different brain regions. Despite shared features, the mechanisms underlying the pathophysiological processes are not known. This review aims at finding, among the genetic-associated cases of PD and AD, common trends that could be of interest to discover reliable biomarkers and efficacious therapies, especially those aimed at affording neuroprotection, i.e., the prevention of neuronal death.
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Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K+-Cl- Cotransporter KCC2.
Tillman, L, Zhang, J
BioMed research international. 2019;:8941046
Abstract
Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.
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Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases.
Collin, F
International journal of molecular sciences. 2019;(10)
Abstract
Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of products of lipid, protein and DNA oxidation in vivo. Even if they participate in cell signaling and metabolism regulation, ROS are also formidable weapons against most of the biological materials because of their intrinsic nature. By nature too, neurons are particularly sensitive to oxidation because of their high polyunsaturated fatty acid content, weak antioxidant defense and high oxygen consumption. Thus, the overproduction of ROS in neurons appears as particularly deleterious and the mechanisms involved in oxidative degradation of biomolecules are numerous and complexes. This review highlights the production and regulation of ROS, their chemical properties, both from kinetic and thermodynamic points of view, the links between them, and their implication in neurodegenerative diseases.
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Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors.
Bähring, R
Channels (Austin, Tex.). 2018;(1):187-200
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Abstract
Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+-binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformationl changes, is well documented for KChIPs. Moreover, the Ca2+ dependence of the presenilin/KChIP complex may be related to Alzheimer's disease and the Ca2+ dependence of the DNA/KChIP complex to pain sensing. However, only in few cases could the Ca2+ binding to KChIPs be directly linked to the control of excitability in nerve and muscle cells known to express Kv4/KChIP channel complexes. This review summarizes current knowledge about the Ca2+ binding properties of KChIPs and the Ca2+ dependencies of macromolecular complexes containing KChIPs, including those with presenilins, DNA and especially Kv4 channels. The respective physiological or pathophysiolgical roles of Ca2+ binding to KChIPs are discussed.
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HIV Associated Neurodegenerative Disorders: A New Perspective on the Role of Lipid Rafts in Gp120-Mediated Neurotoxicity.
Smith, LK, Kuhn, TB, Chen, J, Bamburg, JR
Current HIV research. 2018;(4):258-269
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Abstract
The implementation of combination antiretroviral therapy (cART) as the primary means of treatment for HIV infection has achieved a dramatic decline in deaths attributed to AIDS and the reduced incidence of severe forms of HIV-associated neurocognitive disorders (HAND) in infected individuals. Despite these advances, milder forms of HAND persist and prevalence of these forms of neurocognitive impairment are rising with the aging population of HIV infected individuals. HIV enters the CNS early in the pathophysiology establishing persistent infection in resident macrophages and glial cells. These infected cells, in turn, secrete neurotoxic viral proteins, inflammatory cytokines, and small metabolites thought to contribute to neurodegenerative processes. The viral envelope protein gp120 has been identified as a potent neurotoxin affecting neurodegeneration via indirect and direct mechanisms involving interactions with chemokine co-receptors CCR5 and CXCR4. This short review focuses on gp120 neurotropism and associated mechanisms of neurotoxicity linked to chemokine receptors CCR5 and CXCR4 with a new perspective on plasma membrane lipid rafts as an active participant in gp120-mediated neurodegeneration underlying HIV induced CNS pathology.