TY  - JOUR
AU  - Nakos Bimpos, Modestos
AU  - Karali, Katerina
AU  - Antoniou, Christine
AU  - Palermos, Dionysios
AU  - Fouka, Maria
AU  - Delis, Anastasios
AU  - Tzieras, Iason
AU  - Chrousos, George Panagiotis
AU  - Koutmani, Yassemi
AU  - Stefanis, Leonidas
AU  - Polissidis, Alexia
TI  - Alpha-synuclein-induced stress sensitivity renders the Parkinson's disease brain susceptible to neurodegeneration.
JO  - Acta Neuropathologica Communications
VL  - 12
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2024-00780
SP  - 100
PY  - 2024
AB  - 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.
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: genetics
KW  - Animals
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Humans
KW  - Rats, Transgenic
KW  - Rats
KW  - Stress, Psychological: metabolism
KW  - Stress, Psychological: pathology
KW  - Male
KW  - Corticosterone: blood
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Hypothalamo-Hypophyseal System: metabolism
KW  - Female
KW  - Pituitary-Adrenal System: metabolism
KW  - Parkinson’s disease (Other)
KW  - Alpha-synuclein (Other)
KW  - Chronic stress (Other)
KW  - Corticosterone (Other)
KW  - Glucocorticoids (Other)
KW  - HPA axis (Other)
KW  - Parkinson’s disease (Other)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Corticosterone (NLM Chemicals)
KW  - SNCA protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11181569
C6  - pmid:38886854
DO  - DOI:10.1186/s40478-024-01797-w
UR  - https://pub.dzne.de/record/270308
ER  -