Autism, Asthma and the Regulation of PIN1
As already described in earlier sections, activated DAPK1, in synergy
with p53, promotes the transcriptional activation of BAX, a condition
that results in neuronal cell apoptosis and death [191]. Neural
apoptotic cell death mediated by BAX also implies that PIN1 will be
deactivated by DAPK1 in neurons [86]. Similarly, in eosinophils,
apoptosis is prevented by activated PIN1 in the nucleus, and, by
contrast, apoptosis is magnified by the inhibition of PIN1 [247].
Eosinophils are short-lived cells and, in common with neurons, are
highly differentiated and unable to divide. The activation of BAX in
eosinophils is also crucial for their mitochondrial mediated apoptotic
signaling, in order to prevent the emergence of long-lived eosinophils
that induce inflammation and asthma [248]. The
DAPK1-activation-PIN1-inhibition mediated expression of BAX, which is
important for the control of overwhelming eosinophil migration and
continued activation of long-lived eosinophils, constitutes a primary
pathologic factor in asthma [249].
Although an earlier meta-analysis study had failed to prove a direct
relationship between asthma and autism [250], there are serious
immune defects and comorbidities in autistic individuals that imply a
predisposition to asthma in autistic individuals [251]. Moreover, a
recent research investigation indicates that genetic relationships exist
between autism and asthma [252].
The study of L Guglielmi et al. [253] provides a fine description of
autism spectrum disorder (ASD) associated pathogenesis linked to
potassium (K+) channelopathies. Briefly, in ASD there
is a dysfunction of several K(+) channel types, often with a genetic
link, and these contribute to the repetitive behavior and social and
communication impairments encountered in autism. In the dendrites of
pyramidal neurons, there are numerous transient A-type potassium ion
channels that regulate action potential depolarizations and abnormal
excitatory events [254].
Kv4.2 is one of these crucial
potassium channel hippocampal proteins that controls neuronal plasticity
and holds a central role in learning and memory acquisition [255].
Quite importantly, the functioning of Kv4.2 depends on the activity of
PIN1. When PIN1 becomes activated, it binds dynamically to the Thr-607
phosphorylated form of Kv4.2, leading to the isomerization of the
proline involved at the related pSer/Thr-Pro motif. This causes the
dissociation of Kv4.2 from its dipeptidyl peptidase 6 (DPP6) subunit,
inhibiting the Kv4.2 function for protection from excess neuron
excitability through depolarization [256]. The isomerization induced
by PIN1 in Kv4.2 is important for proper neuronal and cognitive function
[256].
Furthermore, in contrast to PIN1-mediated neuron over-excitability due
to the loss of Kv4.2 function, other studies that relate to Alzheimer’s
disease (AD) indicate that mutations in the synaptic scaffolding
protein, SHANK3, which associates with autism [257], render the loss
of PIN1 activity important for the regulation of synaptic plasticity in
AD [171]. Given the aforementioned evidence, justifiable scientific
grounds suggest a common PIN1-mediated pathogenic mechanism associated
with both asthma and neurological defects encountered in ASD. PIN1 is
significantly implicated in other studies of the pathogenesis of asthma
by inducing eosinophilic inflammation through the upregulation of TGF-β1
[258]. In this concept, the mode of induction or inhibition of
apoptosis by the DAPK1–PIN1 interactive regulation becomes important
for the onset of both asthma and neurologic defects in autism
[86,191].