Strain-Distinct α-Synuclein and Tau Cross-Seeding Uncovered by Correlative Approach with Optical Photothermal Infrared Sub-Micron Imaging
(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
- Zhan, Xiaoni
LU
; Li, Wen
LU
; Hatterer, Eric
; Courade, Jean-Philippe
; Piché, Kristin
; Klementieva, Oxana
LU
and Li, Jia-Yi LU
- organization
-
- MultiPark: Multidisciplinary research focused on Parkinson's disease
- Neural Plasticity and Repair (research group)
- Infect@LU
- LU Profile Area: Light and Materials
- LU Profile Area: Proactive Ageing
- LTH Profile Area: Nanoscience and Semiconductor Technology
- NanoLund: Centre for Nanoscience
- Medical Microspectroscopy (research group)
- publishing date
- 2025-08-06
- 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
-
- scopus:105013157211
- pmid:40726080
- 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
- 2025-10-04 04:08:34
@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}}, }