Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice

Abstract

Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr−/− and aged heterozygous Mthfr+/− mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Bα holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Bα levels in all brain regions examined from aged Mthfr+/+ mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr+/− mice. In turn, the down regulation of PP2A/Bα was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer’s disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD.

Alzheimer’s disease pathogenesis: Is there a role for folate?

“…MTHFR is the rate-limiting enzyme for the conversion of folate to active 5MeTHF, hence knockout mice have elevated Hcy and altered methylation potential (see Figure 1). In young and aged Mthfr knockout mouse models, it was demonstrated that mild MTHFR deficiency decreases methylation of PP2A in a region-specific manner (Sontag et al, 2014). The effects were exacerbated by folate deficiency which significantly decreased methylated PP2A levels associated with increased P-tau.…”

“…Conversely, inducing high plasma Hcy levels (vs. mild as with (Sontag et al, 2014)), caused tau hyperphosphorylation at multiple sites, inhibition of PP2A activity and alterations in the PP2Ac subunit, with methylesterase activation leading to demethylation of PP2Ac (Zhang et al, 2008). Upon administration of folate and B12 the HHcy was reversed preventing tau hyperphosphorylation, inactivation of PP2A and modified activity of PP2Ac but no change was exhibited in GSK3.…”

“…Demethylation of PP2A alters holoenzyme assembly which subsequently does not affect PP2A activity but its substrate specificity through altering subunit composition. This is associated with a shift of A PP processing towards the amyloidogenic pathways triggering P-tau accumulation and increased secretion of A PP fragments (Tolstykh et al, 2000, Sontag andSontag, 2014). These studies provide links between SAH (dietary folate deficiency) to decreases in methylation and subsequent regulation of A PP processing.…”

“…Presenilin expression/activity (Scarpa et al, 2003, Schrötter et al, 2012 ①secretase expression/activity (Scarpa et al, 2003, Fuso et al, 2005, Fuso et al, 2007, Schrötter et al, 2012 Tau phosphorylation (Fuso et al, 2012, Chan et al, 2008b PP2A (Sontag et al, 2014, Yoon et al, 2007, Obeid et al, 2011, Chan et al, 2008b Calcium homeostasis Ö ① ①N ① ①H ① ① ① Oxidative stress (Tjiattas et al, 2004, Cankurtaran et al, 2013, Oikonomidi et al, 2016 Reactive oxygen species (Tchantchou et al, 2004, Ho et al, 2003 GSH et al, 2005, Kalani et al, 2014, Hodgson et al, 2013 Choline (Crivello et al, 2010) Phosphatidyl choline (Troen et al, 2008) Table 1 Summary of the pathways involved in AD and linked to one-carbon metabolism as reviewed here, with reference to Figure 1.…”

“…Inducing a mild vitamin deprivation (Fuso et al, 2005, Sontag et al, 2014) is a useful tool as it represents model similar to that of nutritional insufficiency, producing more archetypal results. Additionally nutrients represent a modifiable risk factor in disease development; increasing understanding could lead to a simple preventative measure.…”