A5049703753- Sphingolipid Metabolism and Signaling
- Lysosomal Storage Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Prion Diseases and Protein Misfolding
- Neurogenesis and neuroplasticity mechanisms
- RNA Research and Splicing
- Lipid Membrane Structure and Behavior
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Cholesterol and Lipid Metabolism
- Lipid metabolism and biosynthesis
- Biomedical Research and Pathophysiology
Virginia Commonwealth University
2019-2025
Children's Hospital of Richmond at VCU
2021
Indian Institute of Technology Hyderabad
2019-2020
Abstract The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex tightly regulated by cellular levels, but sensing mechanism unknown. Here we show that purified human SPT-ORMDL complexes are inhibited central metabolite ceramide. We have solved cryo-EM structure SPT-ORMDL3 a ceramide-bound state. Structure-guided mutational analyses reveal essential...
Myelin is a unique lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical myelin components. Yet sphingolipid content synthesis have not been well characterized in oligodendrocytes, the myelin-producing cells of CNS. Here, using quantitative real-time PCR, LC-MS/MS-based lipid analysis, biochemical assays, we examined during peak period myelination postnatal rat brain. Importantly, production isolated oligodendrocytes. We...
The serine palmitoyltransferase (SPT) complex catalyzes the rate-limiting step in de novo biosynthesis of ceramides, precursors sphingolipids. mammalian ORMDL isoforms (ORMDL1-3) are negative regulators SPT. However, roles individual unclear. Using siRNA against ORMDLs, only single siORMDL3 had modest effects on dihydroceramide and ceramide levels, whereas downregulation all three ORMDLs induced more pronounced increases. With CRISPR/Cas9-based genome-editing strategy, we established stable...
Sphingolipids play crucial roles in cell membrane structure and multiple signaling pathways. Sphingolipid de novo biosynthesis is mediated by the serine palmitoyltransferase (SPT) enzyme complex. Homeostatic regulation of this complex dependent on its regulatory subunit, ORMDLs, which there are three isoforms. It well established that ORMDLs regulate SPT activity, but it still unclear whether ORMDL isoforms have distinct functions properties. Here, we focus understanding physiological...
Niemann-Pick type C1 (NPC1) disease is rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition catabolic-derived sphingolipids, NPC1 dysfunction also leads an increase de novo biosynthesis, yet little known of cellular mechanism involved. Although deletion or inhibition sterol binding domain enhanced surprisingly levels ORMDLs, regulatory subunits serine palmitoyltransferase (SPT), rate-limiting...
Abstract Myelin is a unique, lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical components of myelin. Here we examined sphingolipid synthesis during the peak period myelination in postnatal rat brain. Importantly, made measurements isolated oligodendrocytes, myelin-producing cells central nervous system. We analyzed distribution levels enzymes regulators biosynthetic pathway, with focus on serine palmitoyltransferase...
Abstract TDP-43 is an RNA/DNA-binding protein of versatile physiological functions and it also implicated in the pathogenesis amyotrophic lateral sclerosis (ALS) disease addition to several other proteins such as mutant SOD1 FUS etc. Cytoplasmic mis-localization, liquid-liquid phase separation (LLPS) due RNA depletion aggregation are suggested be important TDP-43-toxicity causing mechanisms for ALS manifestation. So far, therapeutic options extremely minimal ineffective therefore,...
Sphingolipids (SLs) are one of the major lipid types present in eukaryotic cells. SLs not only serve as an important constituent plasma membrane but also bioactive lipids which regulate several signal transduction processes such cell growth and differentiation. The de novo biosynthesis begins endoplasmic reticulum (ER) with condensation serine palmitoyl Co-A by rate-limiting enzyme, palmitoyltransferase (SPT). SPT is homeostatically regulated small ER proteins: ORMDLs mammalian cells Orms...