[
International Worm Meeting,
2019]
Polyglutamine (polyQ) expansions in specific proteins are the genetic determinants of nine different neurodegenerative disorders including Huntington's disease (HD), which causes cognitive and motor impairment in mid-late life and is ultimately fatal. We are interested in understanding the molecular and cell biological processes that are affected by the presence of disease-associated variants of the human huntingtin protein (htt). To this end, we generated a novel model of huntingtin protein aggregation by expressing a disease-associated polyQ-containing N-terminal fragment of 513 amino acids of the htt protein with 128 glutamines (Htt513Q128) in C. elegans body wall muscle cells. As a control, we also expressed a non-disease associated tract of 15 glutamines (Htt513Q15). The animals exhibited polyQ length-dependent aggregation and toxicity. To identify genetic modifiers of htt-associated aggregation and toxicity, we performed ethyl methanesulfonate (EMS) mutagenesis on animals with expanded polyQ in the context of the human htt protein and identified three mutants having either a below or above average aggregate count. Western blot analysis revealed that all mutants had significantly higher levels of polyQ protein in comparison to Htt513Q128-expressing animals. This was true even for animals in which we detected less Htt aggregation, meaning that the normal function of certain genes (or QTLs) exacerbates the aggregation and toxicity of the Htt513Q128 protein.
Garcia Manriquez, Bailey, Strysick, Claire, Papapanagiotou, Julia, Rajasekeran, Prisha, Ryou, Hayeon, Green, Emily, Kikis, Elise
[
International Worm Meeting,
2021]
Environmental degradation caused by human behavior is of great concern for human health and the health of Earth's ecosystems. Air pollution, and, especially, traffic-associated particulate matter (TRAP) is a significant health concern. Epidemiological studies have shown that exposure to TRAP triggers Alzheimer's disease (AD) symptoms. Likewise, controlled laboratory studies in which AD mice were continuously exposed to TRAP revealed an increase in amyloid beta (Abeta) plaques. Abeta plaques are composed of misfolded protein. Their increase could be a direct consequence of the disruption of the proteostasis network or an indirect consequence of neuroinflammation. To determine whether TRAP directly impairs the folding of disease-associated proteins, we utilized C. elegans as a model that lacks a canonical inflammatory response. To this end, we exposed animals expressing Abeta or Huntington's disease-associated polyQ protein to nano-sized traffic-derived particulate matter. We found that TRAP triggered polyQ protein misfolding and increased Abeta toxicity. Together, our data suggest that TRAP may act, at least in part, to trigger disease by disrupting the proteostasis balance.