Sphingolipid activator proteins are required for epidermal permeability barrier formation

Area of Science:

• Dermatology
• Biochemistry
• Molecular Biology

Background:

• The epidermal permeability barrier is crucial for skin homeostasis.
• Extracellular lipid membranes in the stratum corneum, composed mainly of ceramides, maintain this barrier.
• Glucosylceramides are precursors to ceramides, hydrolyzed by beta-glucocerebrosidase (beta-GlcCerase).

Purpose of the Study:

• To investigate the role of prosaposin (pSAP) in epidermal barrier formation and function.
• To elucidate the consequences of pSAP deficiency on epidermal lipid metabolism and stratum corneum structure.

Main Methods:

• Generation of a pSAP-deficient mouse model using targeted deletion and homologous recombination.
• Analysis of epidermal lipid composition, including glucosylceramides and ceramides.
• Histological examination of the stratum corneum, including stratum lucidum and lamellar membranes.

Main Results:

• pSAP deficiency resulted in epidermal glucosylceramide accumulation and reduced ceramide levels.
• Alterations were observed in lipids ester-linked to cornified cell envelope proteins.
• A thickened stratum lucidum with scaling and abnormal lamellar membrane maturation was noted.
• Covalently bound omega-OH-GlcCer was detected in pSAP-deficient epidermis.

Conclusions:

• Prosaposin (pSAP) production is essential for normal epidermal barrier formation and function.
• pSAP deficiency leads to significant alterations in epidermal lipid metabolism and stratum corneum structure.
• Deglucosylation to omega-OH-Cer may not be required before lipid covalent attachment to cornified envelope proteins.