Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Chao Peng, Ronald J. Gathagan, Dustin J. Covell, Coraima Medellin, Anna Stieber, John L. Robinson, Bin Zhang, Rose M. Pitkin, Modupe F. Olufemi, Kelvin C. Luk, John Q. Trojanowski and Virginia M.-Y. Lee ()
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Chao Peng: the Perelman School of Medicine at the University of Pennsylvania
Ronald J. Gathagan: the Perelman School of Medicine at the University of Pennsylvania
Dustin J. Covell: the Perelman School of Medicine at the University of Pennsylvania
Coraima Medellin: the Perelman School of Medicine at the University of Pennsylvania
Anna Stieber: the Perelman School of Medicine at the University of Pennsylvania
John L. Robinson: the Perelman School of Medicine at the University of Pennsylvania
Bin Zhang: the Perelman School of Medicine at the University of Pennsylvania
Rose M. Pitkin: the Perelman School of Medicine at the University of Pennsylvania
Modupe F. Olufemi: the Perelman School of Medicine at the University of Pennsylvania
Kelvin C. Luk: the Perelman School of Medicine at the University of Pennsylvania
John Q. Trojanowski: the Perelman School of Medicine at the University of Pennsylvania
Virginia M.-Y. Lee: the Perelman School of Medicine at the University of Pennsylvania

Nature, 2018, vol. 557, issue 7706, 558-563

Abstract: Abstract In Lewy body diseases—including Parkinson’s disease, without or with dementia, dementia with Lewy bodies, and Alzheimer’s disease with Lewy body co-pathology 1 —α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

Date: 2018
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DOI: 10.1038/s41586-018-0104-4

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