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      Disrupted striatal neuron inputs and outputs in Huntington's disease

      1 , 2 , 1

      CNS Neuroscience & Therapeutics

      Wiley

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          Abstract

          <p id="d5121607e205">Huntington's disease ( <span style="fixed-case">HD</span>) is a hereditary progressive neurodegenerative disorder caused by a <span style="fixed-case">CAG</span> repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N‐terminus of this protein. The <span style="fixed-case">HD</span> pathology resulting from the mutation is most prominent in the striatal part of the basal ganglia, and progressive differential dysfunction and loss of striatal projection neurons and interneurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in striatal neuron dysfunction and loss, based on studies both in human <span style="fixed-case">HD</span> victims and in genetic mouse models of <span style="fixed-case">HD</span>. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in <span style="fixed-case">HD</span>, as well as on the subsequent loss of indirect pathway striatal projection neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic <span style="fixed-case">HD</span>. Later loss of direct pathway striatal projection neurons and their output to the internal pallidal segment account for the severe akinesia seen late in <span style="fixed-case">HD</span>. Loss of parvalbuminergic striatal interneurons may contribute to the late dystonia and rigidity. </p>

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          A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.

          The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.
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            Application of a translational profiling approach for the comparative analysis of CNS cell types.

            Comparative analysis can provide important insights into complex biological systems. As demonstrated in the accompanying paper, translating ribosome affinity purification (TRAP) permits comprehensive studies of translated mRNAs in genetically defined cell populations after physiological perturbations. To establish the generality of this approach, we present translational profiles for 24 CNS cell populations and identify known cell-specific and enriched transcripts for each population. We report thousands of cell-specific mRNAs that were not detected in whole-tissue microarray studies and provide examples that demonstrate the benefits deriving from comparative analysis. To provide a foundation for further biological and in silico studies, we provide a resource of 16 transgenic mouse lines, their corresponding anatomic characterization, and translational profiles for cell types from a variety of central nervous system structures. This resource will enable a wide spectrum of molecular and mechanistic studies of both well-known and previously uncharacterized neural cell populations.
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              Huntington Disease

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                Author and article information

                Journal
                CNS Neuroscience & Therapeutics
                CNS Neurosci Ther
                Wiley
                17555930
                April 2018
                April 2018
                March 26 2018
                : 24
                : 4
                : 250-280
                Affiliations
                [1 ]Department of Anatomy & Neurobiology; The University of Tennessee Health Science Center; Memphis TN USA
                [2 ]Department of Ophthalmology; The University of Tennessee Health Science Center; Memphis TN USA
                Article
                10.1111/cns.12844
                5875736
                29582587
                © 2018

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