Does Glyphosate Suppress PIN1 in Neurons?
DAPK1 is a stress-responsive calcium/calmodulin (Ca2+/CaM) dependent serine/threonine (Ser/Thr) kinase and a mediator of pro-apoptotic cell death [86]. Among its many other functions, DAPK1 phosphorylates PIN1 on Ser71 in the catalytic active site. This phosphorylation fully inactivates PIN1 catalytic activity, as well as inhibiting its nuclear localization. DAPK1 is upregulated in the brains of patients with Alzheimer’s disease, and its overexpression is implicated in Alzheimer’s pathology [87]. Melatonin plays a central role in DAPK1 regulation. It binds to DAPK1 and promotes its ubiquitinization, resulting in its clearance through proteasomal degradation [87].
While melatonin is mainly viewed as a molecule that is produced by the pineal gland in the evening to promote sleep, it is also produced by many other cell types. In particular, microglia synthesize abundant melatonin which can transform them from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Melatonin synthesized by microglia in the cerebellum shortens the pro-inflammatory phase of activated microglia [88]. Melatonin has many beneficial protective effects on regulatory pathways. It significantly decreases DAPK1 expression in a post-transcriptional manner in neuronal cell lines and mouse primary cortical neurons [87]. Melatonin protects from ferroptosis via the Akt/NRF2/Gpx4 signaling pathway. The likely mechanism could be its suppression of DAPK1, which then allows PIN1 activation, and subsequently NRF2 activation through PIN1 binding, a topic we will return to later [89]. While melatonin increases the expression of NRF2, it also decreases the expression of the inflammatory markers TNF-α, IL-1β, IL-6 and inducible nitric oxide synthase (iNOS) [90].
Another way in which PIN1 can become suppressed is through insufficient levels of the antioxidant glutathione in the cell. When glutathione becomes depleted, PIN1 becomes oxidized by hydrogen peroxide, and this inactivates it. The PIN1 active site contains an essential cysteine residue (Cys113), which is very sensitive to oxidation. Treatment of PIN1 with hydrogen peroxide results in the oxidation of Cys113 to sulfinic acid, and this reaction completely disables its isomerase activity [91]. This leads to impaired translocation of NRF2 and p53 to the nucleus, which shuts down their activation of a broad spectrum of enzymes that would normally promote antioxidant defenses and cell survival, respectively. We will have more to say about this in a later section.
We shall see in the next section that glyphosate’s disturbance of glutamate signaling in the brain leads to severe deficiencies of glutathione in neurons.