Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies.

Autor:	Sanderson JB; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., De S; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.; UK Dementia Research Institute, Department of Chemistry, University of Cambridge, Cambridge CB2 0AH, UK., Jiang H; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Rovere M; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Jin M; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Zaccagnini L; UK Dementia Research Institute, Department of Neurology, University College London, London WC1E 6BT, UK., Hays Watson A; UK Dementia Research Institute, Department of Neurology, University College London, London WC1E 6BT, UK., De Boni L; UK Dementia Research Institute, Department of Neurology, University College London, London WC1E 6BT, UK., Lagomarsino VN; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Young-Pearse TL; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Liu X; Department of Chemistry, Rosenstiel Institute for Basic Biomedical Research, Brandeis University, Waltham, MA 02453, USA., Pochapsky TC; Department of Chemistry, Rosenstiel Institute for Basic Biomedical Research, Brandeis University, Waltham, MA 02453, USA., Hyman BT; Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Massachusetts Institute for Neurodegenerative Disease, Boston, MA 02129, USA., Dickson DW; Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA., Klenerman D; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.; UK Dementia Research Institute, Department of Chemistry, University of Cambridge, Cambridge CB2 0AH, UK., Selkoe DJ; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Bartels T; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; UK Dementia Research Institute, Department of Neurology, University College London, London WC1E 6BT, UK.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2020; Vol. 2 (1), pp. fcaa010. Date of Electronic Publication: 2020 Feb 11.
DOI:	10.1093/braincomms/fcaa010
Abstrakt:	Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other 'synucleinopathies'. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity. (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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