With your massive stress from your incompetent doctor not having 100% recovery protocols, your doctor is then required to have EXACT PROTOCOLS that prevent Parkinsons because of your risk of Parkinsons post stroke. Although your doctor will use the excuse this is in rats; no excuses are allowed! Then your doctor should ensure human testing gets done.
Parkinson’s Disease May Have Link to Stroke March 2017
The latest here:
Alpha-synuclein-induced stress sensitivity renders the Parkinson’s disease brain susceptible to neurodegeneration
Acta Neuropathologica Communications volume 12, Article number: 100 (2024)
Abstract
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.
Introduction
On an aging planet, where neurological disorders have become the major cause of disability [1], Parkinson’s disease (PD) is considered the fastest growing neurodegenerative disease [2]. Although more than 95% of PD cases have no identifiable genetic cause [3], the neuronal protein alpha-synuclein (asyn) appears to be a major player in both genetic and idiopathic PD pathogenesis [4]. As it has been quite challenging to recapitulate full-blown PD in rodent models of asyn overexpression, it is believed that additional environmental triggers may be needed for asyn to elicit its pathogenic effect [5].
In 1886, the famous neurologist Sir William Gowers described in the “Manual of Diseases of the Nervous System” that “prolonged anxiety and severe emotional shock often precede the onset of tremor”, one of the most characteristic motor symptoms of PD (then referred to as “paralysis agitans”) [6]. Today, we know that chronic stress and stress hormones affect central nervous system function at all levels: transcriptional regulation, cellular signaling, synaptic function, neurotransmission, glial function, and behavior [7]. While chronic stress has firmly established a causal relation with the pathogenesis of neuropsychiatric diseases such as depression [8], it may also cause dopaminergic neurodegeneration, the hallmark pathology of PD, in susceptible individuals [9], and may accelerate dopaminergic neurodegeneration in PD animal models [10, 11].
To date, no study has comprehensively addressed the risk chronic stress confers, and whether it should be considered a trigger, a facilitator or an aggravator of PD [5]. Clinical evidence alludes to an abnormal stress response, i.e. hypothalamic–pituitary–adrenal (HPA) axis dysregulation, however, direct evidence of molecular and glucocorticoid-mediated pathologies is lacking [12]. Asyn poses a likely culprit as exacerbated asyn pathology has been demonstrated in the A53T mouse model following chronic mild stress [11] and in a model of seeded asyn pathology in mouse striatum following corticosterone administration [13]. However, it is currently unknown if enhanced asyn burden itself is involved in stress dysregulation and vice versa.
To address this issue, we assessed HPA axis function in bacterial artificial chromosome transgenic rats that overexpress human full-length wildtype asyn (BAC). Nine month-old BAC rats model a premotor hyperdopaminergic phenotype, representing a state prior to overt neurodegenerative phenoconversion [14]. Furthermore, we examined the pathological and phenotypic consequences of chronic exogenous corticosterone (CORT) administration to demonstrate that chronic stress can act additively or synergistically with asyn to incite changes related to asyn pathology, neuroinflammation, nigrostriatal neurodegeneration, and non-motor and motor behavioral deficits. Finally, upon finding molecular perturbations in hippocampal stress signaling in BAC rats, we sought to investigate if such changes are conserved in PD patient brains and could potentially be involved in altered sensitivity to chronic stress in the context of PD.
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