Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

Autor: Hübener-Schmid J; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany., Kuhlbrodt K; Evotec SE, Hamburg, Germany., Peladan J; Evotec SE, Hamburg, Germany., Faber J; DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.; Department of Neurology, University Hospital Bonn, Bonn, Germany., Santana MM; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.; Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Hengel H; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Jacobi H; Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany., Reetz K; Department of Neurology, RWTH Aachen University, Aachen, Germany.; JARA-Brain Institute Molecular Neuroscience and Neuroimaging, Jülich, Germany., Garcia-Moreno H; Department of Clinical and Movement Neuroscience, Ataxia Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Raposo M; Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal & Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal., van Gaalen J; Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands., Infante J; Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain., Steiner KM; Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, Essen University Hospital, University of Duisburg-Essen, Essen, Germany., de Vries J; Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Verbeek MM; Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.; Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands., Giunti P; Department of Clinical and Movement Neuroscience, Ataxia Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Pereira de Almeida L; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.; Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Lima M; Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal & Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal., van de Warrenburg B; Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands., Schöls L; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Klockgether T; DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.; Department of Neurology, University Hospital Bonn, Bonn, Germany., Synofzik M; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Riess O; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2021 Nov; Vol. 36 (11), pp. 2675-2681. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1002/mds.28749
Abstrakt: Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers.
Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF).
Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials.
Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases.
Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
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