A5039507484- Glycogen Storage Diseases and Myoclonus
- Lysosomal Storage Disorders Research
- Genetics and Neurodevelopmental Disorders
- Protein Tyrosine Phosphatases
- Carbohydrate Chemistry and Synthesis
- Metabolomics and Mass Spectrometry Studies
- Microbial Metabolites in Food Biotechnology
- Genetic Syndromes and Imprinting
- Enzyme Production and Characterization
- Glycosylation and Glycoproteins Research
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Ubiquitin and proteasome pathways
- Alzheimer's disease research and treatments
- Neurological disorders and treatments
- Cancer, Hypoxia, and Metabolism
- Autoimmune Neurological Disorders and Treatments
- Microtubule and mitosis dynamics
- Advanced Proteomics Techniques and Applications
- Fungal and yeast genetics research
- Neuroscience and Neuropharmacology Research
- Toxoplasma gondii Research Studies
- Food composition and properties
- Phytase and its Applications
- Plant nutrient uptake and metabolism
University of Florida
2022-2025
Florida College
2022-2025
University of Kentucky
2015-2024
University of Massachusetts Chan Medical School
2024
Markey Cancer Center
2019-2023
Epilepsy Foundation
2018-2023
University of Bologna
2023
Istituto delle Scienze Neurologiche di Bologna
2023
University of Manchester
2019
Indiana University
2015
Macrophages use mitochondrial lactate metabolism for ACLY-dependent histone acetylation, immune suppression, and tumor progression.
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role energy homeostasis and has been proposed as therapeutic target multiple storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors this enzyme. Here, we report preclinical characterization MZ-101, small molecule that potently inhibits GYS1 vitro vivo without inhibiting GYS2, related isoform essential for synthesizing liver glycogen....
Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either gene encoding dual-specificity phosphatase, known as laforin, or recently identified the protein malin. Here, we demonstrate that malin single subunit E3 ubiquitin (Ub) ligase and its RING domain necessary sufficient to mediate ubiquitination. Additionally, interacts with polyubiquitinates leading degradation. Missense are present LD patients abolish ability polyubiquitinate signal...
Abstract Starch is the major storage carbohydrate in plants. It comprised of glucans that form semicrystalline granules. Glucan phosphorylation a prerequisite for normal starch breakdown, but phosphoglucan metabolism not understood. A putative protein phosphatase encoded at Excess 4 (SEX4) locus Arabidopsis thaliana was recently shown to be required breakdown. Here, we show SEX4 vivo and define its role within degradation pathway. dephosphorylates both granule surface soluble phosphoglucans...
Laforin is the only phosphatase in animal kingdom that contains a carbohydrate-binding module. Mutations gene encoding laforin result Lafora disease, fatal autosomal recessive neurodegenerative disorder, which diagnosed by presence of intracellular deposits insoluble complex carbohydrates known as bodies. We demonstrate interacts with proteins to be involved glycogen metabolism and rule out several these potential substrates. Surprisingly, we find displays robust activity against...
A newly emerging family of phosphatases that are members the haloacid dehalogenase superfamily contains catalytic motif DXDX(T/V). member this DXDX(T/V) phosphatase known as Dullard was recently shown to be a potential regulator neural tube development in Xenopus [Satow R, Chan TC, Asashima M (2002) Biochem Biophys Res Commun 295:85-91]. Herein, we demonstrate human and yeast protein Nem1p perform similar functions mammalian cells cells, respectively. In addition similarity primary sequence,...
Lafora disease (LD) is an autosomal recessive neurodegenerative that results in progressive myoclonus epilepsy and death. LD caused by mutations either the E3 ubiquitin ligase malin or dual specificity phosphatase laforin. A hallmark of accumulation insoluble glycogen cytoplasm cells from most tissues. Glycogen metabolism regulated phosphorylation key metabolic enzymes. One regulator this protein targeting to (PTG/R5), a scaffold binds both many enzymes involved synthesis, including 1 (PP1),...
Lafora disease (LD) is a progressive myoclonic epilepsy resulting in severe neurodegeneration followed by death. A hallmark of LD the accumulation insoluble polyglucosans called bodies (LBs). caused mutations gene encoding phosphatase laforin, which reportedly exists solely vertebrates. We utilized bioinformatics screen to identify laforin orthologues five protists. These protists evolved from progenitor red alga and synthesize an carbohydrate whose composition closely resembles LBs....
Abstract Starch contains phosphate covalently bound to the C6-position (70 80% of total phosphate) and C3-position (20 30%) glucosyl residues amylopectin fraction. In plants, transient phosphorylation starch renders granule surface more accessible glucan hydrolyzing enzymes is required for proper degradation. Phosphate also confers desired properties starch-derived pastes industrial applications. Arabidopsis thaliana, removal by phosphatase Excess4 (SEX4) essential breakdown. We identified a...
The Apolipoprotein E (APOE) gene is a major genetic risk factor associated with Alzheimer's disease (AD). APOE encodes for three main isoforms in humans (E2, E3, and E4). Homozygous E4 individuals have more than 10-fold higher developing late-onset AD, while E2 carriers are protected. A hallmark of AD reduction cerebral glucose metabolism, alluding to strong metabolic component onset progression. Interestingly, display similar regional pattern hypometabolism decades prior onset. Mapping this...
Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD intracellular accumulation insoluble polysaccharide deposits known as bodies (LBs) brain and other tissues. In mouse models, genetic reduction glycogen synthesis eliminates LB formation rescues neurological phenotype. Therefore, LBs have become therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused...
Abstract Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes brain energy metabolism arise the preclinical phase of AD, suggesting important metabolic component early AD pathology. Neurons astrocytes function close collaboration, which essential for recycling neurotransmitters synapse. However, this crucial interplay during stages development has not been sufficiently...
Abstract Background Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well young cognitively normal carriers of the Ε4 allele Apolipoprotein E (APOE), strongest genetic predictor late-onset AD. While this clinical feature has been described for over two decades, mechanism underlying these changes cerebral metabolism remains a critical knowledge gap field. Methods Here, we undertook multi-omic approach by combining single-cell RNA...
Abstract Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application high-dimensionality reduction/spatial clustering and histopathological annotation matrix datasets to assess tissue metabolic heterogeneity in human lung diseases. Using features identified from this pipeline, hypothesize that channeling between glycogen N-linked...
Cori’s disease is a glycogen storage disorder characterized by deficiency in the debranching enzyme, amylo-1,6-glucosidase,4-α-glucanotransferase (AGL). Here, we demonstrate that G1448R genetic variant of AGL unable to bind and displays decreased stability rescued proteasomal inhibition. more highly ubiquitinated than its wild-type counterpart forms aggresomes upon proteasome impairment. Furthermore, E3 ubiquitin ligase Malin interacts with promotes ubiquitination AGL. known be mutated...
Significance Starch is the main carbohydrate storage molecule in plants and ubiquitous human life. Reversible starch phosphorylation key regulatory event catabolism. Excess4 (SEX4) preferentially dephosphorylates C6 position of glucose its absence results a dramatic accumulation leaf starch. We present structure SEX4 bound to phosphoglucan product, define mechanism specific activity, reverse specificity C3 via mutagenesis. The ability control has direct applications agriculture industrial...