Sjögren-Larsson syndrome: A biochemical rationale for using aldehyde-reactive therapeutic agents.

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.