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Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders.

ABSTRACT: Recent extensive evidence indicates that air pollution, in addition to causing respiratory and cardiovascular diseases, may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is comprised of ambient particulate matter (PM) of different sizes, gases, organic compounds, and metals. An important contributor to PM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Epidemiological and animal studies have shown that exposure to air pollution may be associated with multiple adverse effects on the central nervous system. In addition to a variety of behavioral abnormalities, the most prominent effects caused by air pollution are oxidative stress and neuro-inflammation, which are seen in both humans and animals, and are supported by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered most relevant. Human and animal studies suggest that air pollution may cause developmental neurotoxicity, and may contribute to the etiology of neurodevelopmental disorders, including autism spectrum disorder. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies, such as alpha-synuclein or beta-amyloid, and may thus contribute to the etiopathogenesis of neurodegenerative diseases, particularly Alzheimer's disease and Parkinson's disease.

SUBMITTER: Costa LG

PROVIDER: S-EPMC7245732 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer's disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.

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Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders.

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