Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases.

Autor: Altay MF; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland.; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Kumar ST; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland., Burtscher J; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland., Jagannath S; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland., Strand C; Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, England., Miki Y; Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, England.; Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan., Parkkinen L; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Holton JL; Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, England., Lashuel HA; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland. hilal.lashuel@epfl.ch.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2023 Dec 07; Vol. 9 (1), pp. 161. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1038/s41531-023-00604-y
Abstrakt: The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect the diverse forms of aSyn may lead to inaccurate estimations of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterized an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn, and that recognizes all monomeric, oligomeric, and fibrillar aSyn conformations. Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneous forms of aSyn pathology, rich in Serine 129 phosphorylation, Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered both to neurons and glia. In addition, we show that aSyn can become hyperphosphorylated during processes of aggregation and inclusion maturation in neuronal and animal models of aSyn seeding and spreading. The validation pipeline we describe for these antibodies paves the way for systematic investigations into aSyn pathological diversity in the human brain, peripheral tissues, as well as in cellular and animal models of synucleinopathies.
(© 2023. The Author(s).)
Databáze: MEDLINE
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