陰謀分析_ワク04
SARS-Cov2 関連 書記論文 プリオン、アルツハイマー
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection relies on the binding of S protein (Spike glycoprotein) to ACE (angiotensin converting enzyme) 2 in the host cells. Vascular endothelium(中胚葉起源の上皮) can be infected by SARS-CoV-2, which triggers mitochondrial reactive oxygen species(ROS, 血中活性酸素種, produced by mitochondria) production and glycolytic shift(解糖シフト, glycolysis 解糖系とは、生体内に存在する生化学反応経路の名称であり、グルコースをピルビン酸などの有機酸に分解し、グルコースに含まれる高い結合エネルギーを生物が使いやすい形に変換していくための代謝過程である。ほとんど全ての生物が解糖系を持っており、もっとも原始的な代謝系とされている). Paradoxically, ACE2 is protective in the cardiovascular(心血管) system, and SARS-CoV-1 S protein promotes lung injury by decreasing the level of ACE2 in the infected lungs. In the current study, we show that S protein alone can damage vascular endothelial cells (ECs) by downregulating ACE2 and consequently inhibiting mitochondrial function.
COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS-CoV-2 enters 3D human brain organoids(試験管内など生体外、3次元的につくられた臓器である) within 2 days of exposure. We identified that SARS- CoV-2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS-CoV-2 exposure is associated with altered distribution of Tau from axons to soma, hyper-phosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS-CoV-2 and emphasize that brain organoids could model CNS pathologies of COVID-19.
Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion- like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in the SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike protein, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of the spike protein is particularly interesting, since although the SARS-CoV-2 and SARS-CoV S proteins share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold(10-20倍) higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interact with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified prion-like domains (PrDs) in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interact with RBD have important functional roles in viral adhesion and entry.
- Prion protein as a toxic acceptor of amyloid-β oligomers
The initial report that cellular prion protein (PrPC) mediates toxicity of Amyloid-β (Aβ) species linked to Alzheimer’s disease was initially treated with scepticism, but growing evidence supports this claim. That there is a high-affinity interaction is now clear and its molecular basis is being unravelled whilst recent studies have identified possible down-stream toxic mechanisms. Determination of the clinical significance of such interactions between PrPC and disease-associated Aβ species will require experimental medicine studies in humans. Compounds that inhibit PrP-dependent Aβ toxicity are starting to be trialled in humans and, although it is clear that only a fraction of Alzheimer’s disease toxicity could be governed by PrPC, a partial but still therapeutically useful role in human disease may soon be testable.
- SARS-CoV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration, 2021/3/4
The post-infection of COVID-19 includes a myriad of neurologic symptoms including neurodegeneration. Protein aggregation in brain can be considered as one of the important reasons behind the neuro- degeneration. SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binding proteins. Moreover, heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain. In this paper, we have shown that the SARS-CoV-2 S1 RBD binds to a number of aggregation-prone, heparin binding proteins including Aβ, α-synuclein, tau, prion, and TDP-43 RRM. These interactions suggests that the heparin-binding site on the S1 protein might assist the binding of amyloid proteins to the viral surface and thus could initiate aggregation of these proteins and finally leads to neurodegeneration in brain. The results will help us to prevent future outcomes of neurodegeneration by targeting this binding and aggregation process
- Transmission and spreading of tauopathy in transgenic mouse brain, 2009/7
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process neuronal tau inclusions first appear in transentorhinal cortex, from where they appear to spread to hippocampal formation and neocortex 2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. Abundant tau inclusions, in the absence of β-amyloid deposits, define Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases 1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia 3-5. Thus, transgenic mice expressing mutant (e.g. P301S) human tau in nerve cells exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein 6,7. In contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or display neurodegeneration 7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that the injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces the assembly of wild-type human tau into filaments and the spreading of pathology from the site of injection to neighbouring brain regions.
