Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons
Abstract Parkinson’s disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity a...
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Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-14735-0 |
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| author | Vyron Gorgogietas Amélie Weiss Loïc Cousin David Hoffmann Karen Schmitt Arnaud Ogier Peter A. Barbuti Bruno F. R. Santos Ibrahim Boussaad Annika Wittich Andrea Zaliani Ole Pless Rejko Krüger Peter Sommer Johannes H. Wilbertz |
| author_facet | Vyron Gorgogietas Amélie Weiss Loïc Cousin David Hoffmann Karen Schmitt Arnaud Ogier Peter A. Barbuti Bruno F. R. Santos Ibrahim Boussaad Annika Wittich Andrea Zaliani Ole Pless Rejko Krüger Peter Sommer Johannes H. Wilbertz |
| author_sort | Vyron Gorgogietas |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity and focus on single phenotypes. We used patient-derived SNCA triplication (SNCA-4x) and isogenic control (SNCA-corr) mDA neurons, applying high-content imaging-based morphological profiling to identify and rescue multiple phenotypes. Screening 1,020 compounds, we identified top-scoring compounds that restored healthy profiles in SNCA-4x neurons, increasing Tyrosine hydroxylase (TH) and decreasing α-synuclein (αSyn) levels. Several hits were linked to mitochondrial biology. Tyrphostin A9, a mitochondrial uncoupler, and several of its structural analogues decreased ROS levels, normalized mitochondrial membrane potential, and increased respiration. Western blotting confirmed that Tyrphostin A9 reduces αSyn levels. Our study highlights the neuroprotective potential of mild mitochondrial uncoupling in mDA neurons. |
| format | Article |
| id | doaj-art-b38eeefd90e449bf98dbf68184405ce7 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-b38eeefd90e449bf98dbf68184405ce72025-08-20T04:02:45ZengNature PortfolioScientific Reports2045-23222025-08-0115111810.1038/s41598-025-14735-0Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neuronsVyron Gorgogietas0Amélie Weiss1Loïc Cousin2David Hoffmann3Karen Schmitt4Arnaud Ogier5Peter A. Barbuti6Bruno F. R. Santos7Ibrahim Boussaad8Annika Wittich9Andrea Zaliani10Ole Pless11Rejko Krüger12Peter Sommer13Johannes H. Wilbertz14Luxembourg Centre for Systems Biomedicine (LCSB)KsilinkKsilinkKsilinkKsilinkKsilinkLuxembourg Centre for Systems Biomedicine (LCSB)Luxembourg Centre for Systems Biomedicine (LCSB)Luxembourg Centre for Systems Biomedicine (LCSB)Fraunhofer Institute for Translational Medicine and Pharmacology ITMPFraunhofer Institute for Translational Medicine and Pharmacology ITMPFraunhofer Institute for Translational Medicine and Pharmacology ITMPLuxembourg Centre for Systems Biomedicine (LCSB)KsilinkKsilinkAbstract Parkinson’s disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity and focus on single phenotypes. We used patient-derived SNCA triplication (SNCA-4x) and isogenic control (SNCA-corr) mDA neurons, applying high-content imaging-based morphological profiling to identify and rescue multiple phenotypes. Screening 1,020 compounds, we identified top-scoring compounds that restored healthy profiles in SNCA-4x neurons, increasing Tyrosine hydroxylase (TH) and decreasing α-synuclein (αSyn) levels. Several hits were linked to mitochondrial biology. Tyrphostin A9, a mitochondrial uncoupler, and several of its structural analogues decreased ROS levels, normalized mitochondrial membrane potential, and increased respiration. Western blotting confirmed that Tyrphostin A9 reduces αSyn levels. Our study highlights the neuroprotective potential of mild mitochondrial uncoupling in mDA neurons.https://doi.org/10.1038/s41598-025-14735-0 |
| spellingShingle | Vyron Gorgogietas Amélie Weiss Loïc Cousin David Hoffmann Karen Schmitt Arnaud Ogier Peter A. Barbuti Bruno F. R. Santos Ibrahim Boussaad Annika Wittich Andrea Zaliani Ole Pless Rejko Krüger Peter Sommer Johannes H. Wilbertz Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons Scientific Reports |
| title | Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| title_full | Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| title_fullStr | Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| title_full_unstemmed | Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| title_short | Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| title_sort | morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons |
| url | https://doi.org/10.1038/s41598-025-14735-0 |
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