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

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 -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites . By contrast, in multiple system atrophy α-Syn accumula...

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Bibliographic Details
Published in:Nature (London) 2018-05, Vol.557 (7706), p.558-563
Main Authors: Peng, Chao, Gathagan, Ronald J, Covell, Dustin J, Medellin, Coraima, Stieber, Anna, Robinson, John L, Zhang, Bin, Pitkin, Rose M, Olufemi, Modupe F, Luk, Kelvin C, Trojanowski, John Q, Lee, Virginia M-Y
Format: Article
Language:English
Subjects:
alpha-Synuclein - chemistry
alpha-Synuclein - classification
alpha-Synuclein - metabolism
Alzheimer's disease
Animals
Atrophy
Axons
Cytoplasm - chemistry
Cytoplasm - metabolism
Cytoplasm - pathology
Dementia
Dementia disorders
Female
Humans
Hypotheses
Inclusion bodies
Intracellular
Lewy bodies
Lewy Bodies - chemistry
Lewy Bodies - metabolism
Lewy Bodies - pathology
Lewy body disease
Lewy Body Disease - metabolism
Lewy Body Disease - pathology
Male
Mice
Mice, Inbred C57BL
Movement disorders
Neurodegeneration
Neurodegenerative diseases
Neurons
Neurons - chemistry
Neurons - metabolism
Neurons - pathology
Oligodendrocytes
Oligodendroglia - chemistry
Oligodendroglia - metabolism
Oligodendroglia - pathology
Organ Specificity
Parkinson's disease
Pathology
Protein Folding
Seeds
Synuclein
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Summary: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 -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) . 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-018-0104-4