Folate deficiency leads to increased autophagosome markers
After observing how 5-MTHF (methylfolate, vitamin B9) rapidly reduced OCD symptoms within few days, I got curious to check if folate deficiency has anything to do with stimulating of autophagy which can’t be completed.
I was surprised to find out that folate deficiency does indeed leads to increased markers of incomplete autophagy!
As a reminder: in my hypothesis, incomplete autophagy or impaired proteolysis leads to abnormal reduction of GABA-A receptors, which basically means that GABA regulation is reduced.
FA deficiency significantly increased the formation of autophagosomes and the expression of LC3 and Beclin-1
The results demonstrated that, accompanied by obvious neuron damage, the expression of the autophagic markers LC3 and Beclin-1, and the formation of 8-OHdG (a marker of oxidative stress to DNA) and autophagosomes were significantly increased in the brain cortex after ischemia–reperfusion.
FA deficiency further induced neuronal cell death, and significantly increased the formation of autophagosomes and the expression of LC3 and Beclin-1 in NeuN-positive cell bodies after ischemia–reperfusion.
The elevated level of 8-OHdG was also observed in the ischemic cortex of FA deficiency-treated animals. Conversely, the neuronal cell injury, autophagosome accumulation and the effects of LC3 and Beclin1 overexpression caused by FA deficiency were partially blocked by an autophagic inhibitor 3-methyladenine.
These results suggest that FA deficiency progresses autophagic activation and aggravates the damage in rat brain cortex following focal cerebral ischemia–reperfusion. The oxidative injury may be involved in cell morphological damage and autophagy alteration caused by FA deficiency. (R1)
Folate deficiency inhibits mTOR
We recently reported that mTOR signaling functions as a folate sensor in primary human trophoblast cells, representing a previously unknown molecular mechanism by which folate regulates trophoblast cell function43. Folate sensing by mTOR in PHT cells involves both mTOR Complex 1 and 2 and requires the proton-coupled folate transporter (PCFT).
Herein, we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and placental amino acid transporter activity and causes fetal growth restriction. (R2)
Folate deficiency lowers phosphorylation of Akt
The activation of Akt involves the phosphorylation of two residues. Threonine 308 (Thr308) in the activation loop of Akt is phosphorylated by PDK1, and therefore represents a functional readout of the insulin/IGF-I growth factor signaling pathway. In contrast, serine 473 (Ser473) in the hydrophobic motif is phosphorylated by mTORC2.
The phosphorylation of placental Akt at Ser-473 was markedly decreased in folate deficient mice. Importantly, folate deficiency did not influence Akt phosphorylation at Thr-308 (Fig. 4a,b), suggesting that the impact of low folate on cellular signaling is specific. There was no significant difference in the total Akt expression level between folate deficient and control placentas. (R2)