Submolecular Resolution Imaging of Amyloid Aggregation: An STM Approach to Decipher Missense Mutation Effects in α-Synuclein

Zhun Deng; Zhongyi Jian; Mingzhan Wang; Ruonan Wang; Shanshan Mo; Wenbo Zhang; Yanlian Yang; Chen Wang; Lanlan Yu; Chenxuan Wang

doi:10.1021/acs.nanolett.5c01672

Submolecular Resolution Imaging of Amyloid Aggregation: An STM Approach to Decipher Missense Mutation Effects in α-Synuclein

Zhun Deng (Co-first Author)
, Zhongyi Jian (Co-first Author)
, Mingzhan Wang (Co-first Author)
, Ruonan Wang
, Shanshan Mo
, Wenbo Zhang
, Yanlian Yang
, Chen Wang
, Lanlan Yu^*
, Chenxuan Wang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

Abstract

Intrinsically disordered regions (IDRs) are criticalregulators of cellular function, and their aberrant phase transitionsinto amyloid fibrils underlie the pathogenesis of amyloidosis.Missense mutations modulate IDR aggregation, but mechanismsremain unclear. Here, we investigate the impact of Parkinson’sdisease-associated mutations (A53V and T72M) on the aggregationdynamics of α-synuclein (α-Syn), a prototype protein containingIDRs, using scanning tunneling microscopy (STM). We focused ontwo disease-associated mutations, A53V and T72M, in the fibril-forming fragment (residues 42−78) of α-Syn, and we compared theiraggregation behaviors with the wild-type truncated α-Syn. Asdemonstrated by the STM imaging, mutations remodel the coexisting conformational substates as well as the inter-β-strandinteractions in the aggregates. The A53V and T72M mutations reduce the specific inter-β-strand recognitions, which are correlatedwith the altered aggregation kinetics. This study mechanistically explains how mutations regulate IDR aggregation through changingthe conformational diversity, advancing our understanding of the molecular basis of amyloidosis.
© 2025 American Chemical Society

Original language	English
Pages (from-to)	9677–9685
Number of pages	9
Journal	Nano Letters
Volume	25
Issue number	24
Online published	9 Jun 2025
DOIs	https://doi.org/10.1021/acs.nanolett.5c01672
Publication status	Published - 18 Jun 2025

Funding

The work received support from National Natural Science Foundation of China (92353302, 32471451, 32201243, 32201142), the Beijing Nova Program (20240484521), the CAMS Innovation Fund for Medical Sciences (2023-I2M-QJ-009), the National Key R&D Program of China (2022YFA1205800), the Fundamental Research Funds for the Central Universities (3332024154), State Key Laboratory Special Fund (2060204), and Overseas Expertise Introduction Center for Discipline Innovation (“111 Center”) (BP0820029).

Research Keywords

peptide assembly
conformational ensemble
aggregation
beta-Sheet
STM

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@article{edb680ec5c7844f2a057627108c48198,

title = "Submolecular Resolution Imaging of Amyloid Aggregation: An STM Approach to Decipher Missense Mutation Effects in α-Synuclein",

abstract = "Intrinsically disordered regions (IDRs) are criticalregulators of cellular function, and their aberrant phase transitionsinto amyloid fibrils underlie the pathogenesis of amyloidosis.Missense mutations modulate IDR aggregation, but mechanismsremain unclear. Here, we investigate the impact of Parkinson{\textquoteright}sdisease-associated mutations (A53V and T72M) on the aggregationdynamics of α-synuclein (α-Syn), a prototype protein containingIDRs, using scanning tunneling microscopy (STM). We focused ontwo disease-associated mutations, A53V and T72M, in the fibril-forming fragment (residues 42−78) of α-Syn, and we compared theiraggregation behaviors with the wild-type truncated α-Syn. Asdemonstrated by the STM imaging, mutations remodel the coexisting conformational substates as well as the inter-β-strandinteractions in the aggregates. The A53V and T72M mutations reduce the specific inter-β-strand recognitions, which are correlatedwith the altered aggregation kinetics. This study mechanistically explains how mutations regulate IDR aggregation through changingthe conformational diversity, advancing our understanding of the molecular basis of amyloidosis. {\textcopyright} 2025 American Chemical Society",

keywords = "peptide assembly, conformational ensemble, aggregation, beta-Sheet, STM",

author = "Zhun Deng and Zhongyi Jian and Mingzhan Wang and Ruonan Wang and Shanshan Mo and Wenbo Zhang and Yanlian Yang and Chen Wang and Lanlan Yu and Chenxuan Wang",

year = "2025",

month = jun,

day = "18",

doi = "10.1021/acs.nanolett.5c01672",

language = "English",

volume = "25",

pages = "9677–9685",

journal = "Nano Letters",

issn = "1530-6984",

publisher = "American Chemical Society",

number = "24",

}

Submolecular Resolution Imaging of Amyloid Aggregation: An STM Approach to Decipher Missense Mutation Effects in α-Synuclein. / Deng, Zhun (Co-first Author); Jian, Zhongyi (Co-first Author); Wang, Mingzhan (Co-first Author) et al.
In: Nano Letters, Vol. 25, No. 24, 18.06.2025, p. 9677–9685.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Submolecular Resolution Imaging of Amyloid Aggregation

T2 - An STM Approach to Decipher Missense Mutation Effects in α-Synuclein

AU - Deng, Zhun

AU - Jian, Zhongyi

AU - Wang, Mingzhan

AU - Wang, Ruonan

AU - Mo, Shanshan

AU - Zhang, Wenbo

AU - Yang, Yanlian

AU - Wang, Chen

AU - Yu, Lanlan

AU - Wang, Chenxuan

PY - 2025/6/18

Y1 - 2025/6/18

N2 - Intrinsically disordered regions (IDRs) are criticalregulators of cellular function, and their aberrant phase transitionsinto amyloid fibrils underlie the pathogenesis of amyloidosis.Missense mutations modulate IDR aggregation, but mechanismsremain unclear. Here, we investigate the impact of Parkinson’sdisease-associated mutations (A53V and T72M) on the aggregationdynamics of α-synuclein (α-Syn), a prototype protein containingIDRs, using scanning tunneling microscopy (STM). We focused ontwo disease-associated mutations, A53V and T72M, in the fibril-forming fragment (residues 42−78) of α-Syn, and we compared theiraggregation behaviors with the wild-type truncated α-Syn. Asdemonstrated by the STM imaging, mutations remodel the coexisting conformational substates as well as the inter-β-strandinteractions in the aggregates. The A53V and T72M mutations reduce the specific inter-β-strand recognitions, which are correlatedwith the altered aggregation kinetics. This study mechanistically explains how mutations regulate IDR aggregation through changingthe conformational diversity, advancing our understanding of the molecular basis of amyloidosis. © 2025 American Chemical Society

AB - Intrinsically disordered regions (IDRs) are criticalregulators of cellular function, and their aberrant phase transitionsinto amyloid fibrils underlie the pathogenesis of amyloidosis.Missense mutations modulate IDR aggregation, but mechanismsremain unclear. Here, we investigate the impact of Parkinson’sdisease-associated mutations (A53V and T72M) on the aggregationdynamics of α-synuclein (α-Syn), a prototype protein containingIDRs, using scanning tunneling microscopy (STM). We focused ontwo disease-associated mutations, A53V and T72M, in the fibril-forming fragment (residues 42−78) of α-Syn, and we compared theiraggregation behaviors with the wild-type truncated α-Syn. Asdemonstrated by the STM imaging, mutations remodel the coexisting conformational substates as well as the inter-β-strandinteractions in the aggregates. The A53V and T72M mutations reduce the specific inter-β-strand recognitions, which are correlatedwith the altered aggregation kinetics. This study mechanistically explains how mutations regulate IDR aggregation through changingthe conformational diversity, advancing our understanding of the molecular basis of amyloidosis. © 2025 American Chemical Society

KW - peptide assembly

KW - conformational ensemble

KW - aggregation

KW - beta-Sheet

KW - STM

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:001505603400001

U2 - 10.1021/acs.nanolett.5c01672

DO - 10.1021/acs.nanolett.5c01672

M3 - RGC 21 - Publication in refereed journal

SN - 1530-6984

VL - 25

SP - 9677

EP - 9685

JO - Nano Letters

JF - Nano Letters

IS - 24

ER -

Submolecular Resolution Imaging of Amyloid Aggregation: An STM Approach to Decipher Missense Mutation Effects in α-Synuclein

Abstract

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Research Keywords

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