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Nature. 2018 May;557(7706):558-563. doi: 10.1038/s41586-018-0104-4. Epub 2018 May 9.

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

Author information

1
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
2
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. vmylee@upenn.edu.

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.

PMID:
29743672
PMCID:
PMC5970994
DOI:
10.1038/s41586-018-0104-4
[Indexed for MEDLINE]
Free PMC Article

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