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      Neuro-Cardio Mechanisms in Huntington’s Disease and Other Neurodegenerative Disorders

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          Abstract

          Although Huntington’s disease is generally considered to be a neurological disorder, there is mounting evidence that heart malfunction plays an important role in disease progression. This is perhaps not unexpected since both cardiovascular and nervous systems are strongly connected – both developmentally and subsequently in health and disease. This connection occurs through a system of central and peripheral neurons that control cardiovascular performance, while in return the cardiovascular system works as a sensor for the nervous system to react to physiological events. Hence, given their permanent interconnectivity, any pathological events occurring in one system might affect the second. In addition, some pathological signals from Huntington’s disease might occur simultaneously in both the cardiovascular and nervous systems, since mutant huntingtin protein is expressed in both. Here we aim to review the source of HD-related cardiomyopathy in the light of recently published studies, and to identify similarities between HD-related cardiomyopathy and other neuro-cardio disorders.

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          Most cited references 61

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          Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.

          The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
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            Huntington's disease.

            Huntington's disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties. Typically, onset of symptoms is in middle-age after affected individuals have had children, but the disorder can manifest at any time between infancy and senescence. The mutant protein in Huntington's disease--huntingtin--results from an expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The precise pathophysiological mechanisms of Huntington's disease are poorly understood, but research in transgenic animal models of the disorder is providing insight into causative factors and potential treatments.
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              Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.

              Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.
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                Author and article information

                Affiliations
                1Department of Life Sciences, Imperial College London , London, United Kingdom
                2Imperial College Centre for Synthetic Biology, Imperial College London , London, United Kingdom
                3Department of Epidemiology of Rare Diseases and Neuroepidemiology, University of Medical Sciences , Poznań, Poland
                Author notes

                Edited by: Ovidiu Constantin Baltatu, Anhembi Morumbi University, Brazil

                Reviewed by: Abdu Adem, United Arab Emirates University, United Arab Emirates; Michael Huang, The University of Sydney, Australia

                This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                23 May 2018
                2018
                : 9
                5974550 10.3389/fphys.2018.00559
                Copyright © 2018 Critchley, Isalan and Mielcarek.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Counts
                Figures: 3, Tables: 0, Equations: 0, References: 65, Pages: 8, Words: 0
                Funding
                Funded by: European Research Council 10.13039/501100000781
                Award ID: H2020 - ERC-2014-PoC 641232 - Fingers4Cure
                Categories
                Physiology
                Review

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