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000270308 1001_ $$aNakos Bimpos, Modestos$$b0
000270308 245__ $$aAlpha-synuclein-induced stress sensitivity renders the Parkinson's disease brain susceptible to neurodegeneration.
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000270308 520__ $$aA 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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000270308 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000270308 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000270308 650_2 $$2MeSH$$aAnimals
000270308 650_2 $$2MeSH$$aParkinson Disease: metabolism
000270308 650_2 $$2MeSH$$aParkinson Disease: pathology
000270308 650_2 $$2MeSH$$aHumans
000270308 650_2 $$2MeSH$$aRats, Transgenic
000270308 650_2 $$2MeSH$$aRats
000270308 650_2 $$2MeSH$$aStress, Psychological: metabolism
000270308 650_2 $$2MeSH$$aStress, Psychological: pathology
000270308 650_2 $$2MeSH$$aMale
000270308 650_2 $$2MeSH$$aCorticosterone: blood
000270308 650_2 $$2MeSH$$aBrain: metabolism
000270308 650_2 $$2MeSH$$aBrain: pathology
000270308 650_2 $$2MeSH$$aHypothalamo-Hypophyseal System: metabolism
000270308 650_2 $$2MeSH$$aFemale
000270308 650_2 $$2MeSH$$aPituitary-Adrenal System: metabolism
000270308 650_7 $$2Other$$aParkinson’s disease
000270308 650_7 $$2Other$$aAlpha-synuclein
000270308 650_7 $$2Other$$aChronic stress
000270308 650_7 $$2Other$$aCorticosterone
000270308 650_7 $$2Other$$aGlucocorticoids
000270308 650_7 $$2Other$$aHPA axis
000270308 650_7 $$2Other$$aParkinson’s disease
000270308 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000270308 650_7 $$0W980KJ009P$$2NLM Chemicals$$aCorticosterone
000270308 650_7 $$2NLM Chemicals$$aSNCA protein, human
000270308 7001_ $$0P:(DE-2719)9002032$$aKarali, Katerina$$b1$$udzne
000270308 7001_ $$aAntoniou, Christine$$b2
000270308 7001_ $$aPalermos, Dionysios$$b3
000270308 7001_ $$aFouka, Maria$$b4
000270308 7001_ $$aDelis, Anastasios$$b5
000270308 7001_ $$aTzieras, Iason$$b6
000270308 7001_ $$aChrousos, George Panagiotis$$b7
000270308 7001_ $$aKoutmani, Yassemi$$b8
000270308 7001_ $$aStefanis, Leonidas$$b9
000270308 7001_ $$aPolissidis, Alexia$$b10
000270308 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-024-01797-w$$gVol. 12, no. 1, p. 100$$n1$$p100$$tActa Neuropathologica Communications$$v12$$x2051-5960$$y2024
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