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].