A5085827409- Lysosomal Storage Disorders Research
- Glycogen Storage Diseases and Myoclonus
- Carbohydrate Chemistry and Synthesis
- Cellular transport and secretion
- Trypanosoma species research and implications
- Neuroscience and Neuropharmacology Research
- Amino Acid Enzymes and Metabolism
- Prion Diseases and Protein Misfolding
- Neurogenetic and Muscular Disorders Research
- Electrohydrodynamics and Fluid Dynamics
- Biliary and Gastrointestinal Fistulas
- Glycosylation and Glycoproteins Research
- Diabetes Treatment and Management
- Retinal Development and Disorders
- Multiple and Secondary Primary Cancers
- bioluminescence and chemiluminescence research
- Anorectal Disease Treatments and Outcomes
- Plant Surface Properties and Treatments
- Pineapple and bromelain studies
- Acute Myeloid Leukemia Research
- Trace Elements in Health
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Neuroendocrine Tumor Research Advances
- Hemoglobinopathies and Related Disorders
Maze (United States)
2022-2024
Denali Therapeutics (United States)
2019-2022
University of California, San Francisco
2009-2018
University of California, Berkeley
2011
Institute for Neurodegenerative Disorders
2009
German Center for Neurodegenerative Diseases
2007
An enzyme transport vehicle enables brain delivery of lysosomal enzymes across the blood-brain barrier in mice.
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....
Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...
The phenotypic effect of prions on host cells is influenced by the physical properties prion strain and its level accumulation. In mammalian cell cultures, accumulation determined interplay between de novo formation, catabolism, division, horizontal cell-to-cell transmission. Understanding this dynamic enables analytical modeling protein-based heritability infectivity. Here, we quantitatively measured these competing effects in a subline neuroblastoma (N2a) propose concordant reaction...
Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result storage diseases (GSDs). In muscle, synthesis initiated by enzymes glycogenin-1 (GYG1), which seeds molecule autoglucosylation, synthase-1 (GYS1), extends chain. Although both are required for proper production, nature their interaction has been enigmatic. Here, we present human GYS1:GYG1 complex multiple conformations representing different functional states. We observe an asymmetric...
Pompe disease is a rare genetic disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). This responsible for breaking down glycogen, leading to abnormal accumulation which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated hypothesis that small molecule inhibition glycogen synthase I (GYS1) may reduce content improve dysregulation mouse model disease. To address hypothesis, studied four groups male mice: control group...
Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but physiological mechanisms that normally regulate organelle remain poorly understood. Interestingly, recent human genetic studies have implicated endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs cytosolic pH, role of isoforms has remained unclear. We now find inactivation...
Pompe disease is a rare glycogen storage caused by mutations in the enzyme acid α‐glucosidase (GAA) resulting pathological accumulation of muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA currently sole treatment option for patients disease. ERT burdens frequent intravenous infusions while insufficiently halting progression due incomplete skeletal distribution. Glycogen synthase 1 (GYS1) has been proposed as substrate...
Prion-infected cells accumulate a heterogeneous population of aberrantly folded PrP conformers, including the disease-causing isoform (PrP(Sc)). We found that specific chemicals can modulate levels various conformers in cultured cells. Positively charged polyamidoamines (dendrimers) eliminated protease-resistant (r) PrP(Sc) from prion-infected and induced formation insoluble, protease-sensitive aggregates (designated PrP(A)). Larger, positively more efficaciously PrP(A) cleared rPrP(Sc),...
We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability reduce glycosaminoglycan (GAG) accumulation in brains of mouse model mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) simultaneously measure heparan sulfate dermatan derived...
Glycogen is a large polymer of glucose that functions as an important means storing energy and maintaining homeostasis. synthesis degradation pathways are highly regulated their dysregulation can contribute to disease. storage diseases set disorders arise from improper glycogen metabolism. disease II, known Pompe disease, caused by genetic mutation leads increased in cells tissues, resulting progressive muscle atrophy respiratory decline for patients. One approach treating reduce levels...
Glycogen is a large polymer of glucose that functions as an important means storing energy and maintaining homeostasis. synthesis degradation pathways are highly regulated their dysregulation can contribute to disease. storage diseases set disorders arise from improper glycogen metabolism. disease II, known Pompe disease, caused by genetic mutation leads increased in cells tissues, resulting progressive muscle atrophy respiratory decline for patients. One approach treating reduce levels...
Abstract Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...