PIN1 and Epilepsy
There is a high rate of co-occurrence between autism and epilepsy, and
many genetic defects are linked to both conditions [238,239].
Glyphosate has been shown to cause seizures in round worms, and this
likely occurred through its action as a GABA-A receptor antagonist
[240].
Recent studies reveal the role of PIN1 in the pathological development
of a range of neurodegenerative diseases, which also includes a
significant influence in the pathology of epilepsy. During epileptic
seizures, an abnormal electrophysiology persists in the brain [241].
On the molecular level, the deregulation of synaptic transmissions is
considered as a major contributing factor for epileptic seizures
[242]. The balance of PIN1 isomerase activity would therefore be of
importance for epilepsy, since it regulates the excitatory glutamate,
N-methyl-D-aspartic acid (NMDA) and
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the
inhibitory gamma-aminobutyric acid (GABA) and glycine receptors. All
these receptors are deregulated during epilepsy, as described in the Y
Chen et al. study [243].
The acquisition of epileptic seizures in association with PIN1
deficiency has been observed in both animals and humans with impaired
PIN1 function, suggesting that the expression of PIN1 can inhibit the
symptoms of epilepsy [244]. PIN1 null mice have significantly
increased susceptibility to seizures and develop age-dependent
spontaneous epilepsy [245]. Recent studies in animals show that PIN1
deficiency increases the susceptibility to epileptic seizures upon
chemical stimuli. Moreover, in humans with epilepsy, PIN1 is
significantly downregulated whereas AMPA receptors are overactive. PIN1
deficient mice have a significantly increased risk to seizures, and
humans with epilepsy have increased phosphorylation of CaMKII and
increased levels of AMPA receptors in the neocortex. PIN1 knockout
increases the number of AMPA receptors through hyperphosphorylation of
CaMKII [245]. In animal experiments, CaMKII hyperphosphorylation is
reversed by the restoration of PIN1 expression in the prefrontal cortex
of their brains [245]. Social impairments in animal models of autism
can be ameliorated by antagonists of the AMPA receptors [246]. These
studies suggest that PIN1 upregulation can restore proper neural network
function and cortical synaptic organization in epilepsy.