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

John B. Sanderson, Suman De, Haiyang Jiang, Matteo Rovere, Ming Jin, Ludovica Zaccagnini, Aurelia Hays Watson, Laura De Boni, Valentina N. Lagomarsino, Tracy L. Young-Pearse, Xinyue Liu, Thomas C. Pochapsky, Bradley T. Hyman, Dennis W. Dickson, David Klenerman, Dennis J. Selkoe, Tim Bartels

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numberfcaa010
JournalBrain Communications
Volume2
Issue number1
DOIs
StatePublished - 2020

Keywords

  • human tissue
  • Lewy body dementia
  • neurotoxicity
  • α-synuclein

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience
  • Neurology

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