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J Biol Chem. 2015 Mar 13;290(11):7040-53. doi: 10.1074/jbc.M115.636498. Epub 2015 Jan 20.

Dysfunction of platelet-derived growth factor receptor α (PDGFRα) represses the production of oligodendrocytes from arylsulfatase A-deficient multipotential neural precursor cells.

Author information

1
From the Department of Anatomy and Cell Biology, College of Medicine, and.
2
the Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Illinois 60612 and.
3
the Department of Clinical Chemistry, Sahlgren Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
4
From the Department of Anatomy and Cell Biology, College of Medicine, and mgivogri@uic.edu.

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.

KEYWORDS:

AKT PKB; Arylsulfatase A; Exosome; Glycolipid; Lipid Raft; Lysosomal Storage Disease; Neural Precursor Cells; Oligodendrocyte; PDGFRalpha; Sulfatides

PMID:
25605750
PMCID:
PMC4358127
DOI:
10.1074/jbc.M115.636498
[Indexed for MEDLINE]
Free PMC Article

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