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

Abstract

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.

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…Tau, another Alzheimer’s disease-related protein, was also affected by Mn exposure. Specifically, accumulation of hyperphosphorylated tau under Mn exposure (500–1000 μM for 24 h) was also shown to be associated with demethylation of protein phosphatase 2 A (PP2A) that is known to be one of the key tau phosphatases [ 148 ]. Correspondingly, reversal of PP2A demethylation was associated with reduction of pTau levels, reduced oxidative stress, apoptosis, and improvement in cell viability [ 149 ].…”

Methionine restriction - Association with redox homeostasis and implications on aging and diseases

“…In streptozotocin (STZ) induced diabetic rats H 2 S not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed STZ-disturbed hippocampal neurogenesis and subsequently mediate antidepressant- and anxiolytic-like effects [ 213 ]. In an AD mouse model, pathological features such as excessive Aβ accumulation [ 214 ] and tau hyperphosphorylation [ 215 ] were closely connected to the methionine metabolism. H 2 S as a product of methionine metabolism, decreased extracellular levels of Aβ 40 and Aβ 42 , resulting in improved spatial learning and memory acquisition in APP/PS1 mice [ 216 ].…”

Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation

“…Recent studies have shown that the SAM levels can regulate the methylation patterns of multiple methyl acceptors, such as PP2Ac, in multiple systems (55). The ratio of SAM/SAH is an important metabolic indicator of cell methylation status and can directly affect the activity and expression of methyltransferases (56,57). To determine whether taurine alters the PP2Ac methylation pattern in M1 polarization by affecting the availability of SAM, we used UPLC-MS to detect the levels of SAM and SAH in the cells.…”