Kedia, S;
Fertan, E;
Wu, Y;
Zhang, YP;
Meisl, G;
Lam, JYL;
K. Wiseman, F;
... Klenerman, D; + view all
(2025)
SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy.
Cell Chemical Biology
, 32
(2)
338-351.e4.
10.1016/j.chembiol.2025.01.001.
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Abstract
Synaptic dysfunction is a primary hallmark of both Alzheimer's and Parkinson's disease, leading to cognitive and behavioral decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptopathology. The methodology for studying the small-soluble protein aggregates formed by these proteins is limited. Here we describe SynPull, a method combining single-molecule pull-down, super-resolution microscopy, and advanced computational analyses to characterize the protein aggregates in human and mouse synaptosomes. We show that AT8-positive tau aggregates are the predominant aggregate type in synaptosomes from postmortem Alzheimer's disease brain, although the aggregate size does not change in disease. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in neurodegeneration, elucidating the disease mechanisms causing synaptic dysfunction.
| Type: | Article |
|---|---|
| Title: | SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.chembiol.2025.01.001 |
| Publisher version: | https://doi.org/10.1016/j.chembiol.2025.01.001 |
| Language: | English |
| Additional information: | © 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Alzheimer's disease, Parkinson's disease, dSTORM, data modelling, dementia, mouse model, single-molecule detection, soluble aggregates, super-resolution microscopy, synapse |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205492 |
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