The World Health Organization lists air pollution as one of the top five risks for developing chronic non-communicable disease, joining tobacco use, harmful use of alcohol, unhealthy diets and physical inactivity. This review focuses on how host defense mechanisms against adverse airborne exposures relate to the probable interacting and overlapping pathophysiological features of neurodegeneration and multiple chemical sensitivity. Significant long-term airborne exposures can contribute to oxidative stress, systemic inflammation, transient receptor subfamily vanilloid 1 (TRPV1) and subfamily ankyrin 1 (TRPA1) upregulation and sensitization, with impacts on olfactory and trigeminal nerve function, and eventual loss of brain mass. The potential for neurologic dysfunction, including decreased cognition, chronic pain and central sensitization related to airborne contaminants, can be magnified by genetic polymorphisms that result in less effective detoxification. Onset of neurodegenerative disorders is subtle, with early loss of brain mass and loss of sense of smell. Onset of MCS may be gradual following long-term low dose airborne exposures, or acute following a recognizable exposure. Upregulation of chemosensitive TRPV1 and TRPA1 polymodal receptors has been observed in patients with neurodegeneration, and chemically sensitive individuals with asthma, migraine and MCS. In people with chemical sensitivity, these receptors are also sensitized, which is defined as a reduction in the threshold and an increase in the magnitude of a response to noxious stimulation. There is likely damage to the olfactory system in neurodegeneration and trigeminal nerve hypersensitivity in MCS, with different effects on olfactory processing. The associations of low vitamin D levels and protein kinase activity seen in neurodegeneration have not been studied in MCS. Table 2 presents a summary of neurodegeneration and MCS, comparing 16 distinctive genetic, pathophysiological and clinical features associated with air pollution exposures. There is significant overlap, suggesting potential comorbidity. Canadian Health Measures Survey data indicates an overlap between neurodegeneration and MCS (p < 0.05) that suggests comorbidity, but the extent of increased susceptibility to the other condition is not established. Nevertheless, the pathways to the development of these conditions likely involve TRPV1 and TRPA1 receptors, and so it is hypothesized that manifestation of neurodegeneration and/or MCS and possibly why there is divergence may be influenced by polymorphisms of these receptors, among other factors.

Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity.

Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes - including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 - reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed. 

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Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

ABSTRACT
Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer's disease are susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in Alzheimer's disease patients will affect the pain processing. Here we leverage animal behavior, neural activity recording, optogenetics, chemogenetics and Alzheimer's disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to the pain response. The 5× familial Alzheimer's disease (5×FAD) mice show alleviated mechanical allodynia which can be regained by genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation as well as the dendritic spine reduction of ACC pyramidal neurons in 5×FAD mice can be mimicked by Rac1 or actin polymerization inhibitor in Wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer's disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.

Altered pain sensitivity in 5×FAD mice is associated with the dendritic spine loss in ACC pyramidal neurons.

Supplemental Digital Content is Available in the Text. The 5×FAD mice exhibit reduced spine density in anterior cingulate cortex pyramidal neurons accompanied by alteration of allodynia which can be reversed by optogenetic activation of pyramidal neurons in the anterior cingulate cortex brain region.

https://journals.lww.com/pain/Fulltext/9900/Altered_pain_sensitivity_in_5_familial_Alzheimer.46.aspx

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons

Fbxo45‐mediated NP‐STEP46 degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

Alzheimer disease (AD) is the most common form of dementia, accounting for approximately 60% of cases. In addition to memory loss, changes in pain sensitivity are found in a substantial proportion of patients with AD. However, the mechanism of nociception deficits in AD is still unclear. Here, we hypothesize that the nociception abnormality in AD is due to the aberrant activation of striatal-enriched protein tyrosine phosphatase (STEP) signaling, which modulates proteins related to nociception transduction. Our results indicated that the transgenic mice carrying human amyloid precursor protein (APP) gene had lower sensitivity to mechanical and thermal stimulation than the wild-type group at the ages of 6, 9, and 12 months. These APP mice exhibited elevated STEP activity and decreased phosphorylation of proteins involved in nociception transduction in hippocampi. The pharmacological inhibition of STEP activity using TC-2153 further reversed nociception and cognitive deficits in the APP mice. Moreover, the phosphorylation of nociception-related proteins in the APP mice was also rescued after STEP inhibitor treatment, indicating the key role of STEP in nociception alteration. In summary, this study identifies a mechanism for the reduced nociceptive sensitivity in an AD mouse model that could serve as a therapeutic target to improve the quality of life for patients with AD.

Irene Han Juo Cheng

Papers

Altered nociception in Alzheimer disease is associated with striatal-enriched protein tyrosine phosphatase signaling.