Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Abstract

The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS Sjögren-Larsson syndrome (SLS)2 is a hereditary neurocutaneous disorder caused by mutations in the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2. The major symptoms of SLS are mental retardation, spastic di-or tetraplegia, and ichthyosis, with crystalline macular dystrophy sometimes comorbid (1). ALDH3A2 catalyzes the conversion of fatty aldehydes with medium-chain (MC) to very-long-chain fatty acids (FA) (MC, C5-C10; long-chain (LC), C11-C20; and very-longchain, ՆC21), with the most preferred substrates being C16 and C18 aldehydes (2, 3). To date, more than 70 mutations have been found in the ALDH3A2 gene of SLS patients, and most of them cause Ͼ90% reduction in enzyme activity (4). Because aldehyde molecules are reactive and toxic in general, it is considered that accumulated fatty aldehydes cause the SLS pathology by reacting with certain important proteins in the nervous system and epidermis and compromising their functions. Furthermore, the literature lacks a detailed description of the characteristics of Aldh3a2 knock-out mice.The skin symptom ichthyosis is characterized by dry, thickened, and scaly skin, often likened to fish scales, and is caused by a skin permeability barrier defect related to multilayered lipids (lipid lamellae) in the epidermis. The epidermis is composed of four cell layers, the stratum basale, stratum spinosum, stratum granulosum, and the stratum corneum, the last of which is the site of these lipid lamellae, and accordingly has the most important role in skin barrier formation (5, 6). Keratinocytes proliferate in the stratum basale and migrate outward, differentiating into cell layer-specific cell types. The major lipid components of lipid lamellae are ceramides, cholesterol, and FAs, with ceramides being the most abundant (5, 6). A variety of ceramide species exist in the epidermis. Among them, acylceramides are a class of epidermis-specific ceramides that play an essential role in skin barrier formation (7,8). Ceramides are normally composed of a long-chain base (LCB) and a FA (9). However, acylceramides contain an additional hydrophobic chain (linoleic acid), which is esterified with the hydroxylated -carbon of the FA. In the epidermis of SLS patients, some ceramide species, including the acylceramide EOS (a combination of an esterified -hydroxy FA and the LCB sphingosine), are greatly reduced (10).Several metabolic pathways generate the substrates of ALDH3A2, fatty aldehydes. These include metabolic pathways of leukotriene B 4 , diet-derived phytol, plasmalogens, and fatty alcohols (11)(12)(13)(14)(15). Furthermore, we recently revealed that metabolism of LCBs also generates fatty aldehydes, i.e. hexadecanal (C16:0 aldehyde) from dihydrosphingosine (DHS) and

Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongaseElovl1

“…In fact, we have previously identified similar defects in Aldh3a2 ‐knockout mice using this test . Aldh3a2 ‐knockout mice serve as a model for Sjögren‐Larsson syndrome, an autosomal recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene and characterized by spastic paraplegia and ichthyosis—symptoms also observed in patients with the ELOVL1 mutation. ALDH3A2 is a fatty aldehyde metabolizing enzyme, and Aldh3a2 ‐knockout mice exhibit a decrease in 2‐OH GalCer due to inactivation of FA2H, which synthesizes 2‐OH FAs for 2‐OH GalCer production .…”

Sjogren‐Larsson syndrome associated hypermelanosis

“…In conclusion, ALDH3A2 −/− mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS . The ichthyosis is usually the first signal that brings the patient to medical attention, emphasizing the role of the dermatologist in the diagnosis.…”

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

“…The flow rate was 0.4 mL/min in the binary gradient system by using mobile phase A [acetonitrile/water (3:2, vol/vol) containing 10 mM ammonium formate] and mobile phase B [acetonitrile/2-pronanol (9:1, vol/vol) containing 10 mM ammonium formate]. The elution gradient steps were as follows: 0 min, 40% B; 0-18 min, gradient to 100% B; 18-23 min, 100% B; 23-23.1 min, gradient to 40% B; 23.1-25 min, 40% B. Lipids were detected by multiple reaction monitoring essentially as described (32) by selecting specific m/z at quadrupole mass filters Q1 and Q3 (Tables S1 and S2). Data were analyzed and quantified by using MassLynx software (Waters).…”

“…The Aldh3a2 deficiency causes a reduction in FALDH activity to ∼10% of wild-type CHO-K1 cells (31). We previously revealed that the metabolism of SPH and DHS to esterlinked glycerolipids was reduced in FAA-K1A cells and Aldh3a2 knockout (KO) keratinocytes; instead, SPH and DHS were unusually metabolized to ether-linked glycerolipids, plasmanylethanolamine/ plasmenylethanolamine (PlsE; plasmenylethanolamine, also known as ethanolamine plasmalogen) and plasmanylcholine (PlsC) (21,32). In those cells, unmetabolized fatty aldehydes are reduced to fatty alcohols and then incorporated into ether-linked glycerolipids (Fig.…”