TY - JOUR
T1 - Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies
AU - Sanderson, John B.
AU - De, Suman
AU - Jiang, Haiyang
AU - Rovere, Matteo
AU - Jin, Ming
AU - Zaccagnini, Ludovica
AU - Hays Watson, Aurelia
AU - De Boni, Laura
AU - Lagomarsino, Valentina N.
AU - Young-Pearse, Tracy L.
AU - Liu, Xinyue
AU - Pochapsky, Thomas C.
AU - Hyman, Bradley T.
AU - Dickson, Dennis W.
AU - Klenerman, David
AU - Selkoe, Dennis J.
AU - Bartels, Tim
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Lewy body dementia
KW - human tissue
KW - neurotoxicity
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85089706603&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089706603&partnerID=8YFLogxK
U2 - 10.1093/braincomms/fcaa010
DO - 10.1093/braincomms/fcaa010
M3 - Article
AN - SCOPUS:85089706603
SN - 2632-1297
VL - 2
JO - Brain Communications
JF - Brain Communications
IS - 1
M1 - fcaa010
ER -