2019-01-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/669511Abstract: Protein homeostasis (proteostasis) is regulated by molecular chaperones and protein degradation pathways, such as autophagy-lysosome pathway (autolysosomal pathway or ALP), which is a bulk lysosomal degradative system. While recent studies have recognized that autolysosomal pathway is key in the pathogenesis of PD, it remained unclear how lifestyle activities, such as diets, may modulate autolysosomal pathway and contribute to PD susceptibility. Further, diets determine intestinal microbial composition and metabolism, which has been demonstrated to play a critical role in human health, aging and PD. Little is understood how diets and intestinal microbiota exert effects on PD susceptibility through modulating metabolism and/or ALP. Human α-syn aggregation in C. elegans dopaminergic neurons or PARK mutations results in progressive neuronal loss and motor deficits in C. elegans. Live bacteria cells are colonized in C. elegans gut, forming gut microbiota by early adulthood and their composition tunes host longevity. Yi-Chun Wu lab have employed C. elegans and two different bacteria strains — Comamonas aquatic DA1877 and Escherichia coli OP50 as the bacterial food source to investigate the dietary and intestinal microbial effects on α-syn aggregation. We found that the OP strain decreases α-syn aggregation, likely through increased the autophagic flux. The OP bacterial strain increased the fusion of lysosome to autophagosome during the autolysosomal degradation pathway. Furthermore, the OP50 and DA1877 bacterial strains give rise to differential fatty acid compositions in host C. elegans. Here, we aim to address dietary and microbial effects on synucleopathies and PD susceptibility in human α-syn transgenic worms. In addition to the removal of α-syn aggregates, formation of α-syn aggregates, and factors that regulate the aggregate level and kinetics are also critical, in α-syn accumulation. Shu-Chun Teng lab recently found that phosphorylation can regulate protein folding, protein homeostasis, and life span (under revised in eLIFE) and that, in aged cells, many kinases are mis-regulated, providing the candidate genes that may control α-syn aggregation. Moreover, Chih-Tien Wang lab have successfully generated a rat PD model, in which pathogenic human mutant α-synuclein is transfected into substantia nigra dopaminergic neurons by in vivo electroporation, allowing distribution of human α-syn aggregates across adult rat brain. We will extend our findings to the cell, fly, mouse and rat PD models developed/used by other subprojects and work together to explore the protein phosphorylation network and host-nutrient/microbial cross-talk in regulation of PD pathogenesis. We will examine the possibility that the phosphorylation of the protein folding system would control the accumulation of α-syn. In addition, we will employ the C. elegans overexpressing human pathogenic α-syn to investigate how diets and α-syn proteostasis interact to tune PD susceptibility and the role of the autolysosomal degradation involved. Furthermore, we will work with other subprojects and apply our results to their cell and animal PD models to examine the effects of dietary and microbial compositions on the autolysosomal degradation pathway and PD pathogenesis.Parkinson’s diseaseneurodegenerationα-synucleinLRRK2brain-gut axismicrobiotaautophagylysosomeexosomesystems biology