EMBO Molecular Medicine (Jun 2020)
Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice
- Carlo Wilke,
- Eva Haas,
- Kathrin Reetz,
- Jennifer Faber,
- Hector Garcia‐Moreno,
- Magda M Santana,
- Bart van de Warrenburg,
- Holger Hengel,
- Manuela Lima,
- Alessandro Filla,
- Alexandra Durr,
- Bela Melegh,
- Marcella Masciullo,
- Jon Infante,
- Paola Giunti,
- Manuela Neumann,
- Jeroen de Vries,
- Luis Pereira de Almeida,
- Maria Rakowicz,
- Heike Jacobi,
- Rebecca Schüle,
- Stephan A Kaeser,
- Jens Kuhle,
- Thomas Klockgether,
- Ludger Schöls,
- SCA3 neurofilament study group,
- Christian Barro,
- Jeannette Hübener‐Schmid,
- Matthis Synofzik,
- Christian Deuschle,
- Elke Stransky,
- Kathrin Brockmann,
- Jörg B Schulz,
- Laszlo Baliko,
- Judith van Gaalen,
- Mafalda Raposo,
- Andreas Jeromin
Affiliations
- Carlo Wilke
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- Eva Haas
- Institute of Medical Genetics and Applied Genomics, University of Tübingen
- Kathrin Reetz
- Department of Neurology, RWTH Aachen University
- Jennifer Faber
- Department of Neurology, University Hospital Bonn
- Hector Garcia‐Moreno
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology
- Magda M Santana
- Center for Neuroscience and Cell Biology, University of Coimbra
- Bart van de Warrenburg
- Donders Institute for Brain, Cognition, and Behaviour, Department of Neurology, Radboud University Medical Center
- Holger Hengel
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- Manuela Lima
- Faculdade de Ciências e Tecnologia, Universidade dos Açores
- Alessandro Filla
- Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples
- Alexandra Durr
- Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP‐HP, Inserm, CNRS, University Hospital Pitié‐Salpêtrière
- Bela Melegh
- Department of Medical Genetics, Szentagothai Research Center, University of Pécs Medical School
- Marcella Masciullo
- Spinal Rehabilitation Lab (SPIRE), IRCCS Fondazione Santa Lucia
- Jon Infante
- Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)
- Paola Giunti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology
- Manuela Neumann
- German Center for Neurodegenerative Diseases (DZNE), University of Tübingen
- Jeroen de Vries
- Department of Neurology, University Medical Centre Groningen, University of Groningen
- Luis Pereira de Almeida
- Center for Neuroscience and Cell Biology, University of Coimbra
- Maria Rakowicz
- First Department of Neurology, Institute of Psychiatry and Neurology
- Heike Jacobi
- German Center for Neurodegenerative Diseases (DZNE)
- Rebecca Schüle
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- Stephan A Kaeser
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- Jens Kuhle
- Neurology, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel
- Thomas Klockgether
- Department of Neurology, University Hospital Bonn
- Ludger Schöls
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- SCA3 neurofilament study group
- Christian Barro
- Neurology, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel
- Jeannette Hübener‐Schmid
- Institute of Medical Genetics and Applied Genomics, University of Tübingen
- Matthis Synofzik
- Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen
- Christian Deuschle
- Elke Stransky
- Kathrin Brockmann
- Jörg B Schulz
- Laszlo Baliko
- Judith van Gaalen
- Mafalda Raposo
- Andreas Jeromin
- DOI
- https://doi.org/10.15252/emmm.201911803
- Journal volume & issue
-
Vol. 12,
no. 7
pp. 1 – 19
Abstract
Abstract With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross‐species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock‐in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross‐sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock‐in mice, here also starting already at the presymptomatic stage, closely following ataxin‐3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross‐species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.
Keywords
- knock‐in mouse model
- neurofilament light chain
- phosphorylated neurofilament heavy chain
- presymptomatic stage
- spinocerebellar ataxia type 3
