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.