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Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies
John B Sanderson 1, Suman De 2 3, Haiyang Jiang 1, Matteo Rovere 1, Ming Jin 1, Ludovica Zaccagnini 4, Aurelia Hays Watson 4, Laura De Boni 4, Valentina N Lagomarsino 1, Tracy L Young-Pearse 1, Xinyue Liu 5, Thomas C Pochapsky 5, Bradley T Hyman 6, Dennis W Dickson 7, David Klenerman 2 3, Dennis J Selkoe 1, Tim Bartels 1 4
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.