title: Dysfunction of platelet-derived growth factor receptor α (PDGFRα) represses the production of oligodendrocytes from arylsulfatase A-deficient multipotential neural precursor cells.
abstract: The membrane-bound receptor for platelet-derived growth factor A (PDGFRα) is crucial for controlling the production of oligodendrocytes (OLs) for myelination, but regulation of its activity during OL differentiation is largely unknown. We have examined the effect of increased sulfated content of galactosylceramides (sulfatides) on the regulation of PDGFRα in multipotential neural precursors (NPs) that are deficient in arylsulfatase A (ASA) activity. This enzyme is responsible for the lysosomal hydrolysis of sulfatides. We show that sulfatide accumulation significantly impacts the formation of OLs via deregulation of PDGFRα function. PDGFRα is less associated with detergent-resistant membranes in ASA-deficient cells and showed a significant decrease in AKT phosphorylation. Rescue experiments with ASA showed a normalization of the ratio of long versus short sulfatides, restored PDGFRα levels, corrected its localization to detergent-resistant membranes, increased AKT phosphorylation, and normalized the production of OLs in ASA-deficient NPs. Moreover, our studies identified a novel mechanism that regulates the secretion of PDGFRα in NPs, in glial cells, and in the brain cortex via exosomal shedding. Our study provides a first step in understanding the role of sulfatides in regulating PDGFRα levels in OLs and its impact in myelination.
authors.affiliation: From the Department of Anatomy and Cell Biology, College of Medicine, and.
authors.forename: Katarzyna C
authors.initials: KC
authors.lastname: Pituch
authors.affiliation: From the Department of Anatomy and Cell Biology, College of Medicine, and.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Moyano
authors.affiliation: From the Department of Anatomy and Cell Biology, College of Medicine, and.
authors.forename: Aurora
authors.initials: A
authors.lastname: Lopez-Rosas
authors.affiliation: From the Department of Anatomy and Cell Biology, College of Medicine, and.
authors.forename: Felecia M
authors.initials: FM
authors.lastname: Marottoli
authors.affiliation: the Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: Guannan
authors.initials: G
authors.lastname: Li
authors.affiliation: the Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Hu
authors.affiliation: the Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: Richard
authors.initials: R
authors.lastname: van Breemen
authors.affiliation: the Department of Clinical Chemistry, Sahlgren Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Månsson
authors.affiliation: From the Department of Anatomy and Cell Biology, College of Medicine, and mgivogri@uic.edu.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Givogri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D007966:Leukodystrophy, Metachromatic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D005227:Fatty Acids; D013433:Sulfoglycosphingolipids; D020796:Receptor, Platelet-Derived Growth Factor alpha; D002553:Cerebroside-Sulfatase
keywords: AKT PKB; Arylsulfatase A; Exosome; Glycolipid; Lipid Raft; Lysosomal Storage Disease; Neural Precursor Cells; Oligodendrocyte; PDGFRalpha; Sulfatides