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Strain-Distinct α-Synuclein and Tau Cross-Seeding Uncovered by Correlative Approach with Optical Photothermal Infrared Sub-Micron Imaging

Zhan, Xiaoni LU ; Li, Wen LU ; Hatterer, Eric ; Courade, Jean-Philippe ; Piché, Kristin ; Klementieva, Oxana LU orcid and Li, Jia-Yi LU (2025) In Journal of the American Chemical Society 147(31). p.27323-27340
Abstract

The co-occurrence of α-synuclein (αSyn) and Tau in synucleinopathies and tauopathies suggests a complex interplay between these proteins. Their cross-seeding enhances fibrillization, leading to the formation of diverse amyloid-specific structures enriched with β-sheets, which may influence their biological functions. However, existing tools cannot differentiate structural polymorphs directly in cells, as conventional microscopic approaches have limitations in providing structural insights into aggregates. As a result, a structurally relevant characterization of amyloids in their native cellular environment has not yet been achieved. In this study, we characterize the structural rearrangements of newly formed αSyn inclusions cross-seeded... (More)

The co-occurrence of α-synuclein (αSyn) and Tau in synucleinopathies and tauopathies suggests a complex interplay between these proteins. Their cross-seeding enhances fibrillization, leading to the formation of diverse amyloid-specific structures enriched with β-sheets, which may influence their biological functions. However, existing tools cannot differentiate structural polymorphs directly in cells, as conventional microscopic approaches have limitations in providing structural insights into aggregates. As a result, a structurally relevant characterization of amyloids in their native cellular environment has not yet been achieved. In this study, we characterize the structural rearrangements of newly formed αSyn inclusions cross-seeded by different αSyn and Tau preformed fibrils (PFFs) directly in cells, using a correlative approach that combines submicron optical photothermal infrared (O-PTIR) microspectroscopy and confocal microscopy. We found that hybrid PFFs synthesized from αSyn, and two Tau isoforms (Tau3R and Tau4R) exhibit variations in αSyn and Tau composition. Specifically, structural polymorphs composed of αSyn and Tau3R exhibit the highest β-sheet content and most potent seeding potency, leading to enhanced phosphorylation within cellular inclusions. Importantly, we demonstrate that cellular inclusions inherit structural motifs from their donor seeds and exhibit distinct spatial and structural evolution. By providing subcellular-resolution structural imaging of amyloid proteins, our study uncovers divergent mechanisms of αSyn aggregation induced by αSyn/Tau PFFs in both mixed and hybrid formats.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alpha-Synuclein/chemistry, tau Proteins/chemistry, Humans, Infrared Rays, Amyloid/chemistry
in
Journal of the American Chemical Society
volume
147
issue
31
pages
27323 - 27340
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:40726080
  • scopus:105013157211
ISSN
1520-5126
DOI
10.1021/jacs.5c02811
language
English
LU publication?
yes
id
2b558163-cea4-4683-baac-4777b1d20677
date added to LUP
2025-10-03 12:29:24
date last changed
2025-10-18 05:55:25
@article{2b558163-cea4-4683-baac-4777b1d20677,
  abstract     = {{<p>The co-occurrence of α-synuclein (αSyn) and Tau in synucleinopathies and tauopathies suggests a complex interplay between these proteins. Their cross-seeding enhances fibrillization, leading to the formation of diverse amyloid-specific structures enriched with β-sheets, which may influence their biological functions. However, existing tools cannot differentiate structural polymorphs directly in cells, as conventional microscopic approaches have limitations in providing structural insights into aggregates. As a result, a structurally relevant characterization of amyloids in their native cellular environment has not yet been achieved. In this study, we characterize the structural rearrangements of newly formed αSyn inclusions cross-seeded by different αSyn and Tau preformed fibrils (PFFs) directly in cells, using a correlative approach that combines submicron optical photothermal infrared (O-PTIR) microspectroscopy and confocal microscopy. We found that hybrid PFFs synthesized from αSyn, and two Tau isoforms (Tau3R and Tau4R) exhibit variations in αSyn and Tau composition. Specifically, structural polymorphs composed of αSyn and Tau3R exhibit the highest β-sheet content and most potent seeding potency, leading to enhanced phosphorylation within cellular inclusions. Importantly, we demonstrate that cellular inclusions inherit structural motifs from their donor seeds and exhibit distinct spatial and structural evolution. By providing subcellular-resolution structural imaging of amyloid proteins, our study uncovers divergent mechanisms of αSyn aggregation induced by αSyn/Tau PFFs in both mixed and hybrid formats.</p>}},
  author       = {{Zhan, Xiaoni and Li, Wen and Hatterer, Eric and Courade, Jean-Philippe and Piché, Kristin and Klementieva, Oxana and Li, Jia-Yi}},
  issn         = {{1520-5126}},
  keywords     = {{alpha-Synuclein/chemistry; tau Proteins/chemistry; Humans; Infrared Rays; Amyloid/chemistry}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{31}},
  pages        = {{27323--27340}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of the American Chemical Society}},
  title        = {{Strain-Distinct α-Synuclein and Tau Cross-Seeding Uncovered by Correlative Approach with Optical Photothermal Infrared Sub-Micron Imaging}},
  url          = {{http://dx.doi.org/10.1021/jacs.5c02811}},
  doi          = {{10.1021/jacs.5c02811}},
  volume       = {{147}},
  year         = {{2025}},
}