Diesel exhaust exposure alters the expression of networks implicated in neurodegeneration in zebrafish brains

Abstract

Neurodegenerative diseases are a major cause of disability in the world, but their etiologies largely remain elusive. Genetic factors can only account for a minority of risk for most of these disorders, suggesting environmental factors play a significant role in the development of these diseases. Prolonged exposure to air pollution has recently been identified to increase the risk of Alzheimer’s and Parkinson’s diseases, but the molecular mechanisms by which it acts are not well understood. Zebrafish embryos exposed to diesel exhaust particle extract (DEPe) lead to dysfunctional autophagy and neuronal loss. Here, we exposed zebrafish embryos to DEPe and performed high throughput proteomic and transcriptomic expression analyses from their brains to identify pathogenic pathways induced by air pollution. DEPe treatment altered several biological processes and signaling pathways relevant to neurodegenerative processes, including xenobiotic metabolism, phagosome maturation, and amyloid processing. The biggest induction of gene expression in brains was in Cyp1A (over 30-fold). The relevance of this expression change was confirmed by blocking induction using CRISPR/Cas9, which resulted in a dramatic increase in sensitivity to DEPe toxicity, confirming that Cyp1A induction was a compensatory protective mechanism. These studies identified disrupted molecular pathways that may contribute to the pathogenesis of neurodegenerative disorders. Ultimately, determining the molecular basis of how air pollution increases the risk of neurodegeneration will help in the development of disease-modifying therapies. Graphical abstract

Irisin injection mimics exercise effects on the brain proteome

“…Because of the increasing elderly population in recent years, these age‐dependent disorders are becoming increasingly prevalent (Abbott, 2011; Pringsheim et al, 2014). Several studies indicate that pathological hallmarks of AD are specific lesions due to amyloid plaques containing accumulated proteins amyloid β, neurofibrillary tangles from the hyperphosphorylated of the microtubule‐binding protein tau (Serrano‐Pozo et al, 2011), and for PD is Lewy bodies containing α‐synuclein aggregates (Jami et al, 2021; Kordower et al, 2013). Amyloid β, α‐synuclein and tau proteins are the causative factors of production of reactive species within mitochondria leading to oxidative stress and trigger the release of inflammatory cytokines from microglia and astrocytes, followed by neuronal degeneration (Irwin et al, 2013; Querfurth & LaFerla, 2010).…”

Neurotoxicity of diesel exhaust extracts in zebrafish and its implications for neurodegenerative disease

“…The most upregulated was cyp1a (3.5-fold), a cytochrome P450 enzyme involved in metabolism of drugs and xenobiotics. cyp1a was the highest induced gene in a transcriptomic and proteomic study of larval zebrafish heads with exposure to DEPe 36 . Our results suggest that the olfactory bulb, which likely has the greatest direct exposure to DEPe in this treatment paradigm, may be primarily responsible for this change.…”

“…Our results suggest that the olfactory bulb, which likely has the greatest direct exposure to DEPe in this treatment paradigm, may be primarily responsible for this change. This is an important compensatory mechanism of protection since knocking down cyp1a resulted in an increased sensitivity to DEPe toxicity 36 . Also, there was an upregulation of ugt1b5 (1.36-fold), which is involved in glucuronidation, another pathway involved in the metabolism of toxins and drugs.…”

Air Pollution and the Risk of Parkinson's Disease: A Review

“…DEPe treatment altered several AOPs relevant to PD and other neurodegenerative disorders, including xenobiotic metabolism, phagosome maturation, and amyloid processing. 64 Others have reported CNS inflammation in rodent models similar to that seen in human PD brains. Of interest are the findings that DE increases expression of some inflammatory genes in the olfactory bulb of mice, a brain region where PD pathology is seen very early in the disease.…”

“…We also exposed zebrafish embryos to DEPes and performed proteomic and transcriptomic analyses on brain tissue to identify altered pathogenic pathways. DEPe treatment altered several AOPs relevant to PD and other neurodegenerative disorders, including xenobiotic metabolism, phagosome maturation, and amyloid processing 64 . Others have reported CNS inflammation in rodent models similar to that seen in human PD brains.…”