Rizzo William B, S'aulis Dana, Dorwart Elizabeth, Bailey Zachary
Child Health Research Institute, Omaha, NE, USA.
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
Mol Genet Metab Rep. 2021 Dec 23;30:100839. doi: 10.1016/j.ymgmr.2021.100839. eCollection 2022 Mar.
Sjögren-Larsson syndrome (SLS) is a neurocutaneous disease caused by mutations in that result in deficient fatty aldehyde dehydrogenase (FALDH) activity and impaired fatty aldehyde and fatty alcohol oxidation. The pathogenesis of SLS is thought to involve accumulation of long-chain fatty aldehydes and alcohols and/or metabolically-related ether glycerolipids. Fatty aldehydes are particularly toxic molecules that can covalently react with proteins and certain amino-containing lipids such as phosphatidylethanolamine (PE), generating an unusual aldehyde adduct, N-alkyl-PE (NAPE). Using Faldh-deficient Chinese hamster ovary cells (FAA-K1A) as a cellular model for SLS, we investigated the ability of an aldehyde trapping agent, ADX-102 [2-(3-amino-6-chloro-quinolin-2-yl)-propan-2-ol], to mitigate the harmful effects of fatty aldehydes. FAA-K1A cells were protected from octadecanal (C18:0-al) induced cytotoxicity and apoptosis by ADX-102. Metabolism of C18:0-al to fatty alcohol (octadecanol) was also inhibited by ADX-102. FAA-K1A cells accumulated 5-fold more NAPE with C16- and C18-linked N-alkyl chains compared to wild-type cells, but NAPE levels decreased to normal after growth for 4 days with 50 μM ADX-102. Our results suggest that small aldehyde-reactive molecules, such as ADX-102, should be explored as novel therapeutic agents for SLS by preventing aldehyde adduct formation with critical cellular targets and inhibiting fatty aldehyde metabolism to fatty alcohol.
舍格伦-拉尔松综合征（SLS）是一种神经皮肤疾病，由基因突变导致脂肪醛脱氢酶（FALDH）活性不足以及脂肪醛和脂肪醇氧化受损引起。SLS的发病机制被认为涉及长链脂肪醛和醇以及/或与代谢相关的醚甘油酯的积累。脂肪醛是特别有毒的分子，可与蛋白质和某些含氨基的脂质（如磷脂酰乙醇胺（PE））发生共价反应，生成一种不寻常的醛加合物，N-烷基-PE（NAPE）。我们使用Faldh缺陷的中国仓鼠卵巢细胞（FAA-K1A）作为SLS的细胞模型，研究了一种醛捕获剂ADX-102 [2-(3-氨基-6-氯喹啉-2-基)-丙-2-醇]减轻脂肪醛有害影响的能力。ADX-102保护FAA-K1A细胞免受十八醛（C18:0-al）诱导的细胞毒性和凋亡。ADX-102也抑制了C18:0-al向脂肪醇（十八醇）的代谢。与野生型细胞相比，FAA-K1A细胞积累的具有C16和C18连接的N-烷基链的NAPE多5倍，但在含有50μM ADX-102的条件下生长4天后，NAPE水平降至正常。我们的结果表明，应探索诸如ADX-102之类的小的醛反应性分子作为SLS的新型治疗剂，通过防止醛与关键细胞靶点形成加合物并抑制脂肪醛向脂肪醇的代谢。
