| First Author | Peng C | Year | 2018 |
| Journal | Nature | Volume | 557 |
| Issue | 7706 | Pages | 558-563 |
| PubMed ID | 29743672 | Mgi Jnum | J:262416 |
| Mgi Id | MGI:6159205 | Doi | 10.1038/s41586-018-0104-4 |
| Citation | Peng C, et al. (2018) Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies. Nature 557(7706):558-563 |
| abstractText | 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) -alpha-synuclein (alpha-Syn) aggregates in neurons as Lewy bodies and Lewy neurites (2) . By contrast, in multiple system atrophy alpha-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) (3) . Here we report that pathological alpha-Syn in GCIs and Lewy bodies (GCI-alpha-Syn and LB-alpha-Syn, respectively) is conformationally and biologically distinct. GCI-alpha-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-alpha-Syn in seeding alpha-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-Syn and LB-alpha-Syn show no cell-type preference in seeding alpha-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 alpha-Syn into a GCI-like strain, highlighting the fact that distinct alpha-Syn strains are generated by different intracellular milieus. Moreover, GCI-alpha-Syn maintains its high seeding activity when propagated in neurons. Thus, alpha-Syn strains are determined by both misfolded seeds and intracellular environments. |
