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α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease

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Název: α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
Autoři: Fanni F. Geibl, Martin T. Henrich, Zhong Xie, Enrico Zampese, Jun Ueda, Tatiana Tkatch, David L. Wokosin, Elena Nasiri, Constantin A. Grotmann, Valina L. Dawson, Ted M. Dawson, Navdeep S. Chandel, Wolfgang H. Oertel, D. James Surmeier
Zdroj: Mol Neurodegener
Molecular Neurodegeneration, Vol 19, Iss 1, Pp 1-19 (2024)
Informace o vydavateli: Springer Science and Business Media LLC, 2024.
Rok vydání: 2024
Témata: Dopaminergic, Dopaminergic Neurons, RC952-954.6, Parkinson Disease, Cholinergic Neurons, Mitochondria, Alpha-synuclein, Substantia Nigra, Pedunculopontine nucleus, Mice, Inbred C57BL, Mice, Geriatrics, Parkinson Disease/metabolism [MeSH], Dopaminergic Neurons/metabolism [MeSH], Mice, Inbred C57BL [MeSH], Mitochondria/metabolism [MeSH], Bioenergetics, Cholinergic Neurons/pathology [MeSH], Lewy pathology, Cholinergic Neurons/metabolism [MeSH], Animals [MeSH], Mitochondria/pathology [MeSH], Mice [MeSH], Dopaminergic Neurons/pathology [MeSH], Transcriptome, Electrophysiology, alpha-Synuclein/metabolism [MeSH], Parkinson Disease/pathology [MeSH], Research Article, Parkinson's disease, alpha-Synuclein, Animals, Neurology. Diseases of the nervous system, RC346-429
Popis: Background Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1750-1326
DOI: 10.1186/s13024-024-00756-2
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/39379975
https://doaj.org/article/265447b0a3f045d6bd80bc0702c9544d
https://repository.publisso.de/resource/frl:6493898
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Přístupové číslo: edsair.doi.dedup.....288d1cf892d90377c17f32297d57665e
Databáze: OpenAIRE
Popis
Abstrakt:Background Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
ISSN:17501326
DOI:10.1186/s13024-024-00756-2