Browsing by Author "Faust, Joseph E."

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    Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse
    (Public Library of Science, 2017) Wangler, Michael F.; Chao, Yu-Hsin; Bayat, Vafa; Giagtzoglou, Nikolaos; Shinde, Abhijit Babaji; Putluri, Nagireddy; Coarfa, Cristian; Donti, Taraka; Graham, Brett H.; Faust, Joseph E.; McNew, James A.; Moser, Ann; Sardiello, Marco; Baes, Myriam; Bellen, Hugo J.
    Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD.
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    Peroxisomes Are Required for Lipid Metabolism and Muscle Function in Drosophila melanogaster
    (Public Library of Science, 2014) Faust, Joseph E.; Manisundaram, Arvind; Ivanova, Pavlina T.; Milne, Stephen B.; Summerville, James B.; Brown, H.Alex; Wangler, Michael F.; Stern, Michael; McNew, James A.
    Peroxisomes are ubiquitous organelles that perform lipid and reactive oxygen species metabolism. Defects in peroxisome biogenesis cause peroxisome biogenesis disorders (PBDs). The most severe PBD, Zellweger syndrome, is characterized in part by neuronal dysfunction, craniofacial malformations, and low muscle tone (hypotonia). These devastating diseases lack effective therapies and the development of animal models may reveal new drug targets. We have generated Drosophila mutants with impaired peroxisome biogenesis by disrupting the early peroxin gene pex3, which participates in budding of pre-peroxisomes from the ER and peroxisomal membrane protein localization. pex3 deletion mutants lack detectible peroxisomes and die before or during pupariation. At earlier stages of development, larvae lacking Pex3 display reduced size and impaired lipid metabolism. Selective loss of peroxisomes in muscles impairs muscle function and results in flightless animals. Although, hypotonia in PBD patients is thought to be a secondary effect of neuronal dysfunction, our results suggest that peroxisome loss directly affects muscle physiology, possibly by disrupting energy metabolism. Understanding the role of peroxisomes in Drosophila physiology, specifically in muscle cells may reveal novel aspects of PBD etiology.
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    The Atlastin C-terminal Tail is an Amphipathic Helix that Perturbs Bilayer Structure during Endoplasmic Reticulum Homotypic Fusion
    (American Society for Biochemistry and Molecular Biology, 2015) Faust, Joseph E.; Desai, Tanvi; Verma, Avani; Ulengin, Idil; Sun, Tzu-Lin; Moss, Tyler J.; Betancourt, Miguel A.; Huang, Huey W.; Lee, Tina; McNew, James A.
    Fusion of tubular membranes is required to form three-way junctions found in reticular subdomains of the endoplasmic reticulum (ER). The large GTPase Atlastin has recently been shown to drive ER membrane fusion and three-way junction formation. The mechanism of Atlastin-mediated membrane fusion is distinct from SNARE-mediated and many details remain unclear. In particular, the role of the amphipathic C-terminal tail of Atlastin is still unknown. We have found that a peptide corresponding to the Atlastin C-terminal tail binds to membranes as a parallel alpha helix, induces bilayer thinning, and increases acyl chain disorder. The function of the C-terminal tail is conserved in human Atlastin. Mutations in the C-terminal tail decrease fusion activity in vitro, but not GTPase activity, and impair Atlastin function in vivo. In the context of unstable lipid bilayers, the requirement for the C-terminal tail is abrogated. These data suggest that the C-terminal tail of Atlastin locally destabilizes bilayers to facilitate membrane fusion.