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Dysfunction of Platelet-derived Growth Factor Receptor a (PDGFR alpha) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

Journal article
Authors K. C. Pituch
A. L. Moyano
A. Lopez-Rosas
F. M. Marottoli
G. N. Li
C. Q. Hu
R. van Breemen
Jan-Eric Månsson
M. I. Givogri
Published in Journal of Biological Chemistry
Volume 290
Issue 11
Pages 7040-7053
ISSN 0021-9258
Publication year 2015
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 7040-7053
Language en
Links dx.doi.org/10.1074/jbc.M115.636498
Keywords CENTRAL-NERVOUS-SYSTEM, SPINAL-CORD OLIGODENDROCYTES, METACHROMATIC, LEUKODYSTROPHY, PROGENITOR CELLS, MYELIN MEMBRANE, SONIC HEDGEHOG, LIPID, RAFTS, INTRACELLULAR TRAFFICKING, MULTIVESICULAR ENDOSOMES, RETICULOCYTE, MATURATION, Biochemistry & Molecular Biology
Subject categories Biochemistry and Molecular Biology

Abstract

The membrane-bound receptor for platelet-derived growth factor A (PDGFR alpha) 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 PDGTR alpha 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 PDGFR alpha function. PDGFR alpha 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 PDGTRa 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 PDGFR alpha 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 PDGFR alpha levels in OLs and its impact in myelination.

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