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      PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 2 , 3 , 1 , 1 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 7 , 8 , 7 , 8 , 2 , 3 , 17 , 18 , 19 , 2 , 3 , 20 , 21 , 2 , 3 , 17 , 22 , 15 , 17 , 15 , 15 , 16 , 23 , 23 , 24 , 19 , 25 , 26 , 26 , 27 , 27 , 28 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 36 , 30 , 38 , 39 , 38 , 39 , 40 , 40 , 38 , 41 , 42 , 43 , 42 , 44 , 44 , 44 , 45 , 45 , 45 , 46 , 47 , 48 , 49 , 13 , 2 , 3 , 13 , 50 , 50 , 6 , 10 , 51 , 8 , 9 , 4 , 52 , 53 , 5 , 54 , 55 , 1 , 2 , 3
      Science Translational Medicine
      American Association for the Advancement of Science (AAAS)

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          Abstract

          A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.

          Abstract

          PSMC3 variants associated with neurodevelopmental disorders lead to a type I interferon response by T cells that can be blocked by protein kinase R inhibition.

          Editor’s summary

          Pathogenic proteasome gene variants are associated with a broad spectrum of diseases. Ebstein and colleagues identified 15 de novo missense variants in the PSMC3 proteasome gene in patients with neurodevelopmental delay. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the fly PSMC3 ortholog resulted in learning deficits in the fruit flies. Proteasome dysfunction in T cells from patients with PSMC3 variants led to upregulation of proteotoxic markers and production of interferon type I that could be alleviated by inhibition of protein kinase R. These findings implicate PSMC3 pathogenic variants in neurodevelopmental disorders and suggest a therapeutic strategy for patients carrying these missense mutations. —Daniela Neuhofer

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          The mutational constraint spectrum quantified from variation in 141,456 humans

          Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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            The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences

            The PRoteomics IDEntifications (PRIDE) database ( https://www.ebi.ac.uk/pride/ ) is the world's largest data repository of mass spectrometry-based proteomics data. PRIDE is one of the founding members of the global ProteomeXchange (PX) consortium and an ELIXIR core data resource. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2019. The number of submitted datasets to PRIDE Archive (the archival component of PRIDE) has reached on average around 500 datasets per month during 2021. In addition to continuous improvements in PRIDE Archive data pipelines and infrastructure, the PRIDE Spectra Archive has been developed to provide direct access to the submitted mass spectra using Universal Spectrum Identifiers. As a key point, the file format MAGE-TAB for proteomics has been developed to enable the improvement of sample metadata annotation. Additionally, the resource PRIDE Peptidome provides access to aggregated peptide/protein evidences across PRIDE Archive. Furthermore, we will describe how PRIDE has increased its efforts to reuse and disseminate high-quality proteomics data into other added-value resources such as UniProt, Ensembl and Expression Atlas.
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              The neuropathological diagnosis of Alzheimer’s disease

              Alzheimer’s disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer’s disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer’s disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer’s disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer’s disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer’s disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment. Electronic supplementary material The online version of this article (10.1186/s13024-019-0333-5) contains supplementary material, which is available to authorized users.
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                Journal
                Science Translational Medicine
                Sci. Transl. Med.
                American Association for the Advancement of Science (AAAS)
                1946-6234
                1946-6242
                May 31 2023
                May 31 2023
                : 15
                : 698
                Affiliations
                [1 ]Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany.
                [2 ]Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.
                [3 ]Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, 44000 Nantes, France.
                [4 ]Institut für Medizinische Physik und Biophysik, Universität Leipzig, Medizinische Fakultät, Härtelstr. 16-18, 04107 Leipzig, Germany.
                [5 ]Department of Pediatrics, University of Alberta, Edmonton, AB CT6G 1C9, Canada.
                [6 ]Research Center of Quebec CHU-Université Laval, Québec, QC PQ G1E6W2, Canada.
                [7 ]Department of Neuroscience, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.
                [8 ]ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.
                [9 ]Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.
                [10 ]Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
                [11 ]Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
                [12 ]Neuroscience Research Institute, Peking University; Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing 100191, China.
                [13 ]Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany.
                [14 ]Klinik für Pädiatrie I, Universitätsklinikum Halle (Saale), 06120 Halle (Saale), Germany.
                [15 ]Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130-4899, USA.
                [16 ]GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
                [17 ]Department of Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, Netherlands.
                [18 ]Department of Clinical Genetics, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
                [19 ]Disciplines of Genomic Medicine & Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2145, Australia.
                [20 ]APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC Déficience Intellectuelle et Autisme, 75013 Paris, France.
                [21 ]Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, 75013, Paris, France.
                [22 ]Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, Netherlands.
                [23 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
                [24 ]Genetics Center and Division of Medical Genetics, Children’s Hospital of Orange County, Orange, CA 92868, USA.
                [25 ]Sydney Genome Diagnostics, Western Sydney Genetics Program, Children’s Hospital at Westmead, Sydney, NSW, 2145, Australia.
                [26 ]Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France.
                [27 ]Department of Clinical Research, Ambry Genetics, Aliso Viejo, CA 92656, USA.
                [28 ]Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.
                [29 ]Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children’s Hospital, Seattle, WA 98195-6320, USA.
                [30 ]Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA.
                [31 ]Division of Genetics, St. Luke's Clinic, Boise, ID 83712, USA.
                [32 ]Department of Pediatrics, Division of Pediatric Neurology, UT Health Science Center at San Antonio, San Antonio, TX 78229, USA.
                [33 ]Institute of Human Genetics, Technical University of Munich, School of Medicine, 81675 Munich, Germany.
                [34 ]Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
                [35 ]Klinikum der Universität München, Integriertes Sozialpädiatrisches Zentrum, 80337 Munich, Germany.
                [36 ]Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
                [37 ]Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
                [38 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
                [39 ]Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
                [40 ]Division of Medical Genetics, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
                [41 ]Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, City Hospital Campus, the Gables, Gate 3, Hucknall Road, Nottingham NG5 1PB, UK.
                [42 ]Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
                [43 ]Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19146, USA.
                [44 ]Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, 75743 Paris, France.
                [45 ]University Children’s Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
                [46 ]UMR 1253, iBrain, Université de Tours, Inserm, 37032 Tours, France.
                [47 ]Service de Génétique, Centre Hospitalier Régional Universitaire, 37032 Tours, France.
                [48 ]Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
                [49 ]Deutsches Rheumaforschungszentrum, an institute of the Leibniz Association, Berlin and Berlin Institute of Health, 10117 Berlin, Germany.
                [50 ]Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Abteilung für Funktionelle Genomforschung, 17487 Greifswald, Germany.
                [51 ]Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
                [52 ]Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.
                [53 ]Berlin Institute of Health, 10178 Berlin, Germany.
                [54 ]Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.
                [55 ]Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada.
                Article
                10.1126/scitranslmed.abo3189
                37256937
                962a5a0b-cfbc-40a3-8382-1a05d22ace3e
                © 2023

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