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      CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease

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          Abstract

          Dysregulation of cholesterol synthesis is implicated in Huntington’s disease. Boussicault et al. show that expression of CYP46A1, the rate-limiting enzyme in cholesterol degradation, is reduced in patients and a mouse model. Restoration of CYP46A1 re-establishes normal cholesterol levels and is neuroprotective, suggesting that targeting cholesterol degradation may have therapeutic potential.

          Abstract

          Dysregulation of cholesterol synthesis is implicated in Huntington’s disease. Boussicault et al. show that expression of CYP46A1, the rate-limiting enzyme in cholesterol degradation, is reduced in patients and a mouse model. Restoration of CYP46A1 re-establishes normal cholesterol levels and is neuroprotective, suggesting that targeting cholesterol degradation may have therapeutic potential.

          Abstract

          Huntington’s disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington’s disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington’s disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington’s disease mouse model and in ST hdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington’s disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected ST hdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington’s disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington’s disease.

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          Most cited references48

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          Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells.

          Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that are candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.
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            Autophagy in Huntington disease and huntingtin in autophagy.

            Autophagy is an important biological process that is essential for the removal of damaged organelles and toxic or aggregated proteins by delivering them to the lysosome for degradation. Consequently, autophagy has become a primary target for the treatment of neurodegenerative diseases that involve aggregating proteins. In Huntington disease (HD), an expansion of the polyglutamine (polyQ) tract in the N-terminus of the huntingtin (HTT) protein leads to protein aggregation. However, HD is unique among the neurodegenerative proteinopathies in that autophagy is not only dysfunctional but wild type (wt) HTT also appears to play several roles in regulating the dynamics of autophagy. Herein, we attempt to integrate the recently described novel roles of wtHTT and altered autophagy in HD.
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              Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease.

              Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.
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                Author and article information

                Journal
                Brain
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                March 2016
                29 January 2016
                29 January 2016
                : 139
                : 3
                : 953-970
                Affiliations
                1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France
                2 INSERM U1169, Le Kremlin-Bicêtre, MIRCEN CEA and Université Paris-Sud, Université Paris Saclay, 91400 Orsay, France
                3 Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités- Université Pierre et Marie Curie-Paris 6, CHU Saint-Antoine, 75012 Paris, France
                4 Development and Neuropharmacology, Center for Interdisciplinary Research in Biology, INSERM CNRS 7141. Collège de France
                5 Cellular Imaging Facility, Institute of Biology Paris-Seine CNRS FR, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, Paris, France
                6 Laboratory of Experimental Neurology, Université Libre de Bruxelles, Belgium
                7 Semel Institute, University California Los Angeles, Los Angeles, USA
                8 Department of Translational Medicine and Neurogenetics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), UMR 7104 CNRS/UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, France
                Author notes
                Correspondence to: Dr Jocelyne Caboche, Neurosciences Paris Seine, INSERM/UMR-S 1130; CNRS/UMR 8246 Université Pierre et Marie Curie-Paris 6, 7 Quai Saint Bernard; Paris 75005, France E-mail: jocelyne.caboche@ 123456upmc.fr
                Correspondence may also be addressed to: Dr Sandrine Betuing, E-mail: sandrine.betuing@ 123456upmc.fr

                * ,# These authors contributed equally to this work.

                Article
                awv384
                10.1093/brain/awv384
                4766376
                26912634
                4f3a3918-3ca0-4c08-99c7-643a78e710e7
                © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 10 April 2015
                : 30 October 2015
                : 4 November 2015
                Page count
                Pages: 18
                Categories
                Original Articles
                1060

                Neurosciences
                cyp46a1,cholesterol,striatum,huntington’s disease,neuroprotection
                Neurosciences
                cyp46a1, cholesterol, striatum, huntington’s disease, neuroprotection

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