Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation

Abstract

Alzheimer's disease (AD) neuropathology is characterized by the accumulation of phosphorylated tau and amyloid-␤ peptides derived from the amyloid precursor protein (APP). Elevated blood levels of homocysteine are a significant risk factor for many age-related diseases, including AD. Impaired homocysteine metabolism favors the formation of S-adenosylhomocysteine, leading to inhibition of methyltransferase-dependent reactions. Here, we show that incubation of neuroblastoma cells with S-adenosylhomocysteine results in reduced methylation of protein phosphatase 2A (PP2A), a major brain Ser/Thr phosphatase, most likely by inhibiting PP2A methyltransferase (PPMT). PP2A methylation levels are also decreased after ectopic expression of PP2A methylesterase in Neuro-2a (N2a) cells. Reduced PP2A methylation promotes the downregulation of B␣-containing holoenzymes, thereby affecting PP2A substrate specificity. It is associated with the accumulation of both phosphorylated tau and APP isoforms and increased secretion of ␤-secretase-cleaved APP fragments and amyloid-␤ peptides. Conversely, incubation of N2a cells with S-adenosylmethionine and expression of PPMT enhance PP2A methylation. This leads to the accumulation of dephosphorylated tau and APP species and increased secretion of neuroprotective ␣-secretase-cleaved APP fragments. Remarkably, hyperhomocysteinemia induced in wild-type and cystathionine-␤-synthase ϩ/Ϫ mice by feeding a high-methionine, low-folate diet is associated with increased brain S-adenosylhomocysteine levels, PPMT downregulation, reduced PP2A methylation levels, and tau and APP phosphorylation. We reported previously that downregulation of neuronal PPMT and PP2A methylation occur in affected brain regions from AD patients. The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder.

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

“…Consistent with this observation, LCMT1 downregulation associated with reduced PR55/Ba expression has been observed in AD brains and shown to contribute to Tau hyperphosphorylation and neurodegeneration [61]. Similarly, in mice, hyperhomocysteinemia-induced increased levels of brain S-adenosylhomocysteine is associated with reduced PP2A methylation [62].…”

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

“…Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).PP2A methylation is catalyzed in vivo by the methyl transferase, leucine carboxyl methyltransferase 1 (LCMT-1) (20)(21)(22), and its demethylation is catalyzed by the methylesterase, protein phosphatase methylesterase 1 (PME-1) (23-25). To explore the role of PP2A in AD further, we generated lines of transgenic mice that overexpress these enzymes and tested their effect on the sensitivity of animals to electrophysiogical and behavioral impairments caused by β-amyloid (Aβ).…”

“…8 and 9). Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).…”

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

“…In assessing the regulatory parameters that might control PP2A carboxyl methylation in the CNS, there has been a focus on factors that underlie methylation metabolism such as levels of the methyl donor, S‐adenosylmethionine (SAM), the competitive inhibitor, S‐adenosyl homocysteine (SAH), or the methylation cycle intermediate homocysteine. Accordingly, there is considerable evidence that SAM and SAH levels play a substantial role in regulating PP2A 30, 31, 32, 33, 34. Conditions of methylation and one carbon stress have been shown to cause DNA hypomethylation at loci that appear to contribute to the pathogenesis of PD 35, 36, 37.…”