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.
The proteostasis network comprises the biochemical pathways that together maintain and regulate proper protein synthesis, transport, folding, and degradation. Many neurodegenerative diseases are characterized by a 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 in mice. This suggests that the ability to maintain proteostasis is likely compromised in Alzheimer ‘s disease (AD) pathogenesis upon exposure to nPM. We aim to determine whether this aspect of the environment interacts with proteostasis network machinery to trigger protein misfolding. This could at least partially explain how air pollution exacerbates the symptoms of neurodegenerative diseases of aging, such as AD. We hypothesize that nPM challenges the buffering capacity of the proteostasis network by reducing the efficiency of folding for metastable proteins, thereby disrupting what has proven to be a very delicate proteostasis balance. We will test this hypothesis using C. elegans as our model system. Specifically, we will determine the impact of particulate air pollution on the aggregation and toxicity of disease-associated reporters of proteostasis and on transcriptional responses to stress.
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