Browsing by Author "Thies, Jennifer L."

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    Lipase regulation of cellular fatty acid homeostasis as a Parkinson's disease therapeutic strategy
    (Nature Portfolio, 2022) Fanning, Saranna; Cirka, Haley; Thies, Jennifer L.; Jeong, Jooyoung; Niemi, Sarah M.; Yoon, Joon; Ho, Gary P. H.; Pacheco, Julian A.; Dettmer, Ulf; Liu, Lei; Clish, Clary B.; Hodgetts, Kevin J.; Hutchinson, John N.; Muratore, Christina R.; Caldwell, Guy A.; Caldwell, Kim A.; Selkoe, Dennis; Harvard University; Brigham & Women's Hospital; Harvard Medical School; University of Alabama Tuscaloosa; Harvard T.H. Chan School of Public Health; Massachusetts Institute of Technology (MIT); Broad Institute
    Synucleinopathy (Parkinson's disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein alpha-synuclein (alpha S) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced alpha S inclusions. Patient alpha S triplication vs. corrected neurons had increased pSer129 and insoluble alpha S and decreased alpha S tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in alpha S E46K-expressing human neurons. LIPE reduction in vivo alleviated alpha S-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.
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    No Country for Old Worms: A Systematic Review of the Application of C. elegans to Investigate a Bacterial Source of Environmental Neurotoxicity in Parkinson's Disease
    (MDPI, 2018) Caldwell, Kim A.; Thies, Jennifer L.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham
    While progress has been made in discerning genetic associations with Parkinson's disease (PD), identifying elusive environmental contributors necessitates the application of unconventional hypotheses and experimental strategies. Here, we provide an overview of studies that we conducted on a neurotoxic metabolite produced by a species of common soil bacteria, Streptomyces venezuelae (S. ven), indicating that the toxicity displayed by this bacterium causes stress in diverse cellular mechanisms, such as the ubiquitin proteasome system and mitochondrial homeostasis. This dysfunction eventually leads to age and dose-dependent neurodegeneration in the nematode Caenorhabditis elegans. Notably, dopaminergic neurons have heightened susceptibility, but all of the neuronal classes eventually degenerate following exposure. Toxicity further extends to human SH-SY5Y cells, which also degenerate following exposure. Additionally, the neurons of nematodes expressing heterologous aggregation-prone proteins display enhanced metabolite vulnerability. These mechanistic analyses collectively reveal a unique metabolomic fingerprint for this bacterially-derived neurotoxin. In considering that epidemiological distinctions in locales influence the incidence of PD, we surveyed soils from diverse regions of Alabama, and found that exposure to similar to 30% of isolated Streptomyces species caused worm dopaminergic neurons to die. In addition to aging, one of the few established contributors to PD appears to be a rural lifestyle, where exposure to soil on a regular basis might increase the risk of interaction with bacteria producing such toxins. Taken together, these data suggest that a novel toxicant within the Streptomyces genus might represent an environmental contributor to the progressive neurodegeneration that is associated with PD.
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    Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in C. elegans
    (MDPI, 2023) Thies, Jennifer L.; Willicott, Karolina; Craig, Maici L.; Greene, Madeline R.; DuGay, Cassandra N.; Caldwell, Guy A.; Caldwell, Kim A.; University of Alabama Tuscaloosa; University of Alabama Birmingham
    Oxidative stress is a contributing factor to Parkinson's disease (PD). Considering the prevalence of sporadic PD, environmental exposures are postulated to increase reactive oxygen species and either incite or exacerbate neurodegeneration. We previously determined that exposure to the common soil bacterium, Streptomyces venezuelae (S. ven), enhanced oxidative stress and mitochondrial dysfunction in Caenorhabditis elegans, leading to dopaminergic (DA) neurodegeneration. Here, S. ven metabolite exposure in C. elegans was followed by RNA-Seq analysis. Half of the differentially identified genes (DEGs) were associated with the transcription factor DAF-16 (FOXO), which is a key node in regulating stress response. Our DEGs were enriched for Phase I (CYP) and Phase II (UGT) detoxification genes and non-CYP Phase I enzymes associated with oxidative metabolism, including the downregulated xanthine dehydrogenase gene, xdh-1. The XDH-1 enzyme exhibits reversible interconversion to xanthine oxidase (XO) in response to calcium. S. ven metabolite exposure enhanced XO activity in C. elegans. The chelation of calcium diminishes the conversion of XDH-1 to XO and results in neuroprotection from S. ven exposure, whereas CaCl2 supplementation enhanced neurodegeneration. These results suggest a defense mechanism that delimits the pool of XDH-1 available for interconversion to XO, and associated ROS production, in response to metabolite exposure.