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Title: Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice
Authors: Wilke, Carlo
Haas, Eva
Reetz, Kathrin
Faber, Jennifer
Garcia-Moreno, Hector
Santana, Magda M. 
van de Warrenburg, Bart
Hengel, Holger
Lima, Manuela 
Filla, Alessandro
Durr, Alexandra
Melegh, Bela
Masciullo, Marcella
Infante, Jon
Giunti, Paola
Neumann, Manuela
de Vries, Jeroen
Almeida, Luís Pereira de 
Rakowicz, Maria
Jacobi, Heike
Schüle, Rebecca
Kaeser, Stephan A.
Kuhle, Jens
Klockgether, Thomas
Schöls, Ludger
Barro, Christian
Hübener-Schmid, Jeannette
Synofzik, Matthis
Keywords: knock-in mouse model; neurofilament light chain; phosphorylated neurofilament heavy chain; presymptomatic stage; spinocerebellar ataxia type 3
Issue Date: 7-Jul-2020
Publisher: Wiley-Blackwell
Project: Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), 
National Ataxia Foundation (grant to CW and MS), 
Wilhelm Vaillant Stiftung (grant to CW), 
EU Joint Programme— Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417 
grant NKFIH 119540 
Medical Faculty of the University of Heidelberg 
University of Basel (PhD Program in Health Sciences) 
Serial title, monograph or event: EMBO Molecular Medicine
Volume: 12
Issue: 7
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.
DOI: 10.15252/emmm.201911803
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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