Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies
| Autor: | Thomas C. Pochapsky, Tracy L. Young-Pearse, Bradley T. Hyman, John B. Sanderson, Laura de Boni, Dennis J. Selkoe, Xinyue Liu, Suman De, Valentina N. Lagomarsino, Haiyang Jiang, Ming Jin, Aurelia Hays Watson, Dennis W. Dickson, David Klenerman, Tim Bartels, Ludovica Zaccagnini, Matteo Rovere |
|---|---|
| Přispěvatelé: | Sanderson, John B [0000-0002-1168-2540], Rovere, Matteo [0000-0002-3260-4955], Dickson, Dennis W [0000-0001-7189-7917], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Synucleinopathies Membrane permeability Dementia with Lewy bodies Chemistry Neurodegeneration General Engineering Neurotoxicity Human brain medicine.disease human tissue 3. Good health Pathogenesis 03 medical and health sciences α-synuclein 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Biochemistry Cerebral cortex neurotoxicity medicine Original Article Lewy body dementia 030217 neurology & neurosurgery |
| Zdroj: | Brain Communications |
| ISSN: | 2632-1297 |
| DOI: | 10.1093/braincomms/fcaa010 |
| Popis: | 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. Previous work suggests the existence of soluble, diffusible α-synuclein species in the brains of synucleinopathy patients. In this study, we show that soluble, non-physiological α-synuclein in dementia with Lewy bodies brains permeabilize lipid membranes in vitro compared with identically prepared extracts from control brains. In addition, we show that Lewy-associated species from these brains are neurotoxic. Graphical Abstract Graphical Abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|