Home > Publications Database > Alpha-synuclein-induced stress sensitivity renders the Parkinson's disease brain susceptible to neurodegeneration. > print

001     270308
005     20240809090117.0
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Nakos Bimpos, Modestos
|b 0
245 _ _ |a Alpha-synuclein-induced stress sensitivity renders the Parkinson's disease brain susceptible to neurodegeneration.
260 _ _ |a London
|c 2024
|b Biomed Central
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a A link between chronic stress and Parkinson's disease (PD) pathogenesis is emerging. Ample evidence demonstrates that the presynaptic neuronal protein alpha-synuclein (asyn) is closely tied to PD pathogenesis. However, it is not known whether stress system dysfunction is present in PD, if asyn is involved, and if, together, they contribute to neurodegeneration. To address these questions, we assess stress axis function in transgenic rats overexpressing full-length wildtype human asyn (asyn BAC rats) and perform multi-level stress and PD phenotyping following chronic corticosterone administration. Stress signaling, namely corticotropin-releasing factor, glucocorticoid and mineralocorticoid receptor gene expression, is also examined in post-mortem PD patient brains. Overexpression of human wildtype asyn leads to HPA axis dysregulation in rats, while chronic corticosterone administration significantly aggravates nigrostriatal degeneration, serine129 phosphorylated asyn (pS129) expression and neuroinflammation, leading to phenoconversion from a prodromal to an overt motor PD phenotype. Interestingly, chronic corticosterone in asyn BAC rats induces a robust, twofold increase in pS129 expression in the hypothalamus, the master regulator of the stress response, while the hippocampus, both a regulator and a target of the stress response, also demonstrates elevated pS129 asyn levels and altered markers of stress signalling. Finally, defective hippocampal stress signalling is mirrored in human PD brains and correlates with asyn expression levels. Taken together, our results link brain stress system dysregulation with asyn and provide evidence that elevated circulating glucocorticoids can contribute to asyn-induced neurodegeneration, ultimately triggering phenoconversion from prodromal to overt PD.
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650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a alpha-Synuclein: genetics
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Parkinson Disease: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Rats, Transgenic
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
650 _ 2 |a Stress, Psychological: metabolism
|2 MeSH
650 _ 2 |a Stress, Psychological: pathology
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Corticosterone: blood
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Hypothalamo-Hypophyseal System: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Pituitary-Adrenal System: metabolism
|2 MeSH
650 _ 7 |a Parkinson’s disease
|2 Other
650 _ 7 |a Alpha-synuclein
|2 Other
650 _ 7 |a Chronic stress
|2 Other
650 _ 7 |a Corticosterone
|2 Other
650 _ 7 |a Glucocorticoids
|2 Other
650 _ 7 |a HPA axis
|2 Other
650 _ 7 |a Parkinson’s disease
|2 Other
650 _ 7 |a alpha-Synuclein
|2 NLM Chemicals
650 _ 7 |a Corticosterone
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650 _ 7 |a SNCA protein, human
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700 1 _ |a Karali, Katerina
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700 1 _ |a Antoniou, Christine
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700 1 _ |a Palermos, Dionysios
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700 1 _ |a Fouka, Maria
|b 4
700 1 _ |a Delis, Anastasios
|b 5
700 1 _ |a Tzieras, Iason
|b 6
700 1 _ |a Chrousos, George Panagiotis
|b 7
700 1 _ |a Koutmani, Yassemi
|b 8
700 1 _ |a Stefanis, Leonidas
|b 9
700 1 _ |a Polissidis, Alexia
|b 10
773 _ _ |a 10.1186/s40478-024-01797-w
|g Vol. 12, no. 1, p. 100
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|t Acta Neuropathologica Communications
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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