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Nanoparticulate air pollution disrupts proteostasis in Caenorhabditis elegans.

ABSTRACT: The proteostasis network comprises the biochemical pathways that together maintain and regulate proper protein synthesis, transport, folding, and degradation. Many progressive neurodegenerative diseases, such as Huntington's disease (HD) and Alzheimer's disease (AD), are characterized by an age-dependent failure of the proteostasis network to sustain the health of the proteome, resulting in protein misfolding, aggregation, and, often, neurotoxicity. Although important advances have been made in recent years to identify genetic risk factors for neurodegenerative diseases, we still know relatively little about environmental risk factors such as air pollution. Exposure to nano-sized particulate air pollution, referred to herein as nanoparticulate matter (nPM), has been shown to trigger the accumulation of misfolded and oligomerized amyloid beta (Aβ) in mice. Likewise, air pollution is known to exacerbate symptoms of AD in people. We asked whether nPM contributes to the misfolded protein load, thereby overwhelming the proteostasis network and triggering proteostasis decline. To address this, we utilized C. elegans that express reporter proteins that are sensitive to changes in the protein folding environment and respond by misfolding and displaying readily scorable phenotypes, such as localized YFP fluorescence or paralysis. We found that nPM exacerbated protein aggregation in body wall muscle cells, increasing the number of large visible protein aggregates, the amount of high molecular weight protein species, and proteotoxicity. Taken together, the data point to nPM negatively impacting proteostasis. Therefore, it seems plausible that nPM exposure may exacerbate symptoms of AD and age-related dementia in a manner that is at least partially dependent on proteostasis decline.

SUBMITTER: Garcia Manriquez BA

PROVIDER: S-EPMC9949623 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Nanoparticulate air pollution disrupts proteostasis in Caenorhabditis elegans.

Garcia Manriquez Bailey A BA Papapanagiotou Julia A JA Strysick Claire A CA Green Emily H EH Kikis Elise A EA

PloS one 20230223 2

The proteostasis network comprises the biochemical pathways that together maintain and regulate proper protein synthesis, transport, folding, and degradation. Many progressive neurodegenerative diseases, such as Huntington's disease (HD) and Alzheimer's disease (AD), are characterized by an age-dependent failure of the proteostasis network to sustain the health of the proteome, resulting in protein misfolding, aggregation, and, often, neurotoxicity. Although important advances have been made in ...[more]

PMID: 36821635

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Project description:Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

Dataset Information

Nanoparticulate air pollution disrupts proteostasis in Caenorhabditis elegans.

Publications

Nanoparticulate air pollution disrupts proteostasis in Caenorhabditis elegans.

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