Leucine Carboxyl Methyltransferase Downregulation and Protein Phosphatase Methylesterase Upregulation Contribute Toward the Inhibition of Protein Phosphatase 2A by α-Synuclein

Tian, Hao; Lu, Yongquan; Liu, Jia; Liu, Weijin; Lu, Lingling; Duan, Chaojun; Gao, Ge; Yang, Hui

doi:10.3389/fnagi.2018.00173

Cited by 18 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, we also found that the hypoxia-induced decline in PP2A activity was reversed when α-syn or p-α-syn was interfered with, suggesting that hypoxia-induced PP2A inhibition and α-syn pathology are mutually reinforcing vicious cycles. This hypothesis has been confirmed by previous studies [ 26 , 27 ]. In conclusion, our study highlighted the role of α-syn pathology in chronic hypoxia-induced cognitive impairment and revealed a novel underlying mechanism, providing reliable targets for future research.…”

Section: Discussionsupporting

confidence: 91%

Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation

Liu

Guo

et al. 2022

Cell Death Discov.

Self Cite

View full text Add to dashboard Cite

Chronic hypoxia leads to irreversible cognitive impairment, primarily due to hippocampal neurodegeneration, for which the underlying mechanism remains poorly understood. We administered hypoxia (13%) to C57BL mice for 1–14 days in this study. Chronic hypoxia for 7 or 14 d, but not 1 or 3 d, resulted in alpha-synuclein hyperphosphorylation at serine129 (α-Syn p-S129) and protein aggregation, hippocampal neurodegeneration, and cognitive deficits, whereas the latter could be prevented by alpha-synuclein knockdown or an administered short peptide competing at α-Syn S129. These results suggest that α-Syn p-S129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2α and HIF-2α-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for α-syn, is inhibited, leading to the sustained induction of α-Syn p-S129. Finally, we found that intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-Syn p-S129. These results proved the critical role of α-syn pathology in chronic hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying α-syn hyperphosphorylation during chronic hypoxia. The findings bear implications in developing novel therapeutic interventions for chronic hypoxia-related brain disorders.

show abstract

Section: Discussionsupporting

confidence: 91%

Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation

Liu

Guo

et al. 2022

Cell Death Discov.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, we also found that the hypoxia-induced decline in PP2A activity was reversed when α-syn or p-α-syn was interfered with, suggesting that hypoxia-induced PP2A inhibition and α-syn pathology are mutually reinforcing vicious cycles. This hypothesis has been con rmed by previous studies [30,31]. In conclusion, our study highlighted the role of α-syn pathology in chronic hypoxia-induced cognitive impairment and revealed a novel underlying mechanism, providing reliable targets for future research.…”

Section: Discussionsupporting

confidence: 87%

Chronic hypoxia leads to cognitive impairment by promoting HIF-2 alpha -mediated alpha-synuclein hyperphosphorylation

Jia

Guo

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Cognitive impairment is involved in various central nervous system diseases. Hypoxia is a critical common factor that induces cognitive impairment, but its specific molecular mechanism remains unclear. Understanding the mechanism of cognitive impairment induced by hypoxia will provide potential molecular targets for the intervention of cognitive disorders.Methods: We used hypoxic chambers to establish a chronic hypoxic model in mice. Cognitive impairment, hippocampal neurodegeneration, and alpha-synuclein (α-syn) pathology were assessed in these mice. The α-syn knockout mice or mice administered a competing peptide targeting serine 129 (ser129) were used to investigate the role and molecular mechanism of α-syn pathology in chronic hypoxia-induced cognitive impairment. Finally, we investigated the protective role of intermittent hypoxia preconditioning in chronic hypoxia-induced α-syn pathology and cognitive impairment.Results: Chronic hypoxia resulted in α-syn hyperphosphorylation at ser129 and protein aggregation, hippocampal neurodegeneration, and irreversible cognitive deficits. The latter could be reversed by α-syn knockdown or an administered short peptide competing at α-syn ser129. These results suggest that α-syn hyperphosphorylation at ser129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2α and HIF-2α-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for α-syn, is inhibited, leading to sustained induction of α-syn hyperphosphorylation and aggregation. Finally, we found that enhancing hypoxia tolerance through intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-syn pathology. Conclusion: These results proved the critical role of α-syn pathology in hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying hypoxic-specific induction of cognitive impairment. The findings bear implications in developing novel therapeutic interventions for hypoxia-related cognitive disorders.

show abstract

“…In addition, a marked reduction in LCMT-1 and an increase in PME-1 were observed in our Mn-exposed models in vitro and in vivo. The simultaneous abnormal expression of these two key enzymes regulating PP2Ac methylation has also been confirmed to occur in multiple pathological processes, including AD [28,67,68]. Past studies have confirmed that long-term SAM deficiency or elevated SAH will inhibit not only the activity but also the expression of LCMT-1 in neuronal cells, and our data emphasize the link between LCMT-1 expression and the SAM/SAH ratio in Mn neurotoxicity [69].…”

Section: Discussionsupporting

confidence: 76%

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models

Cai

Tang

et al. 2020

Neurotherapeutics

View full text Add to dashboard Cite

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

show abstract

Leucine Carboxyl Methyltransferase Downregulation and Protein Phosphatase Methylesterase Upregulation Contribute Toward the Inhibition of Protein Phosphatase 2A by α-Synuclein

Cited by 18 publications

References 43 publications

Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation

Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation

Chronic hypoxia leads to cognitive impairment by promoting HIF-2 alpha -mediated alpha-synuclein hyperphosphorylation

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models

Contact Info

Product

Resources

About