α-Synuclein Aggregation Intermediates form Fibril Polymorphs with Distinct Prion-like Properties.
J Mol Biol
; 434(19): 167761, 2022 10 15.
Article
in En
| MEDLINE
| ID: mdl-35907572
ABSTRACT
α-Synuclein (α-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. The mechanism of how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure-function relationship of two polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), based on α-Syn aggregation intermediates. These polymorphs display the structural differences as demonstrated by solid-state NMR and mass spectrometry studies and also possess different cellular activities such as seeding, internalization, and cell-to-cell transfer of aggregates. HMFs, with a compact core structure, exhibit low seeding potency but readily internalize and transfer from one cell to another. The less structured PMFs lack transcellular transfer ability but induce abundant α-Syn pathology and trigger the formation of aggresomes in cells. Overall, the study highlights that the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prions
/
Alpha-Synuclein
/
Protein Aggregation, Pathological
Limits:
Humans
Language:
En
Journal:
J Mol Biol
Year:
2022
Document type:
Article