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      Role of cholesterol and sphingolipids in brain development and neurological diseases

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          Abstract

          Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.

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          Most cited references42

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          Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation.

          α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of experimental and theoretical approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its soluble state to the aggregated state that is associated with neurodegeneration and to its associated disease states.
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            Is Open Access

            A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior

            Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.
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              Cholesterol metabolism and homeostasis in the brain

              Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.
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                Author and article information

                Contributors
                gh_azer@hotmail.com , ghulamhussain@gcuf.edu.pk
                taosun@hqu.edu.cn
                Journal
                Lipids Health Dis
                Lipids Health Dis
                Lipids in Health and Disease
                BioMed Central (London )
                1476-511X
                25 January 2019
                25 January 2019
                2019
                : 18
                : 26
                Affiliations
                [1 ]ISNI 0000 0004 0637 891X, GRID grid.411786.d, Department of Physiology, Faculty of Life Sciences, , Government College University, ; Faisalabad, Pakistan
                [2 ]ISNI 0000 0000 8895 903X, GRID grid.411404.4, Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, , Huaqiao University, ; Xiamen, 361021 Fujian Province China
                [3 ]ISNI 0000 0004 0637 891X, GRID grid.411786.d, Department of Zoology, Faculty of Life Sciences, , Government College University, ; Faisalabad, Pakistan
                [4 ]ISNI 0000 0004 0637 891X, GRID grid.411786.d, Institute of Home and Food Sciences, , Government College University, ; Faisalabad, Pakistan
                [5 ]ISNI 0000 0004 0637 891X, GRID grid.411786.d, Department of Bioinformatics and Biotechnology, , Government College University, ; Faisalabad, Pakistan
                [6 ]ISNI 0000 0000 9284 9490, GRID grid.418920.6, Department of Biosciences, COMSATS Institute of Information Technology, ; Islamabad, Pakistan
                [7 ]GRID grid.461128.8, Department of Neurology, , Allied Hospital, ; Faisalabad, Pakistan
                [8 ]ISNI 0000 0004 0447 0237, GRID grid.419397.1, Human Molecular Genetics Laboratory, Health Biotechnology Division, , National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, ; Faisalabad, Pakistan
                Article
                965
                10.1186/s12944-019-0965-z
                6347843
                30683111
                4b2ed8ce-e96e-4d05-9f0d-6a5579573361
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 19 July 2018
                : 6 January 2019
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Biochemistry
                cholesterol,sphingolipids,development,neurological diseases,nervous system
                Biochemistry
                cholesterol, sphingolipids, development, neurological diseases, nervous system

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