Angelova, Plamena R;
Esteras, Noemi;
Evans, James;
Kostic, Marko;
Melki, Ronald;
Prehn, Jochen HM;
Gandhi, Sonia;
(2025)
α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.
Redox Biology
, 86
, Article 103817. 10.1016/j.redox.2025.103817.
Preview |
Text
Evans_1-s2.0-S2213231725003301-main.pdf Download (15MB) | Preview |
Abstract
One of the major histopathological features of Parkinsons's disease - intracellular Lewy bodies - consists of misfolded α-synuclein. This protein can self-assemble, spread through the brain and seed its own aggregation. Aggregated α-synuclein is shown to induce mitochondrial dysfunction that leads to neuronal loss. Using human iPSC-derived SNCA triplication (3xSNCA) and isogenic control (ISO) neurons we studied whether acute exposure to fibrillar α-synuclein, or its seeding properties, induce effects on mitochondrial function and toxicity. Chronic exposure of neurons to fibrillar α-synuclein (up to 3 weeks) induces a gradual increase of endogenous α-synuclein seeding in neurons, with a decrease in the exogenous fibrillar α-synuclein in ISO and 3xSNCA neurons. Application of exogenous fibrillar α-synuclein induced mitochondrial depolarisation, impairment of complex I function, increased ROS production, oxidative stress and cell death. Notably, α-synuclein seeding following weeks of incubation almost completely restored mitochondrial function and redox balance of human neurons. Thus, mitochondrial dysfunction and oxidative stress in human neurons can be induced acutely only by transient exogenous fibrillar α-synuclein, but seeding is irrelevant to long-term mitochondrial dysfunction or toxicity. This study also indicates an acute, transient toxic insult followed by a remarkable period of adaptation and functional recovery, highlighting the resilience of human neurons.
| Type: | Article |
|---|---|
| Title: | α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.redox.2025.103817 |
| Publisher version: | https://doi.org/10.1016/j.redox.2025.103817 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Neurotoxicity, Parkinson's disease, Seeding, Snca, α-synuclein |
| 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 > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10212749 |
Archive Staff Only
 |
View Item |
