Neural symptoms in a gene knockout mouse model of Sjögren‐Larsson syndrome are associated with a decrease in 2‐hydroxygalactosylceramide

Abstract

Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjögren-Larsson syndrome (SLS) is one such disorder, which is caused by mutations in the fatty aldehyde dehydrogenase ALDH3A2. To date, the molecular mechanism underlying SLS pathology has remained unknown. In this study, we found that Aldh3a2 is expressed in oligodendrocytes and neurons in the mouse brain, and neurons of Aldh3a2 knockout (KO) mice exhibited impaired metabolism of the long-chain base, a component of sphingolipids. Aldh3a2 KO mice showed several abnormalities corresponding to SLS symptoms in behavioral tests, including increased paw slips on a balance beam and light-induced anxiety. In their brain tissue, 2-hydroxygalactosylceramide, an important lipid for myelin function and maintenance, was reduced by the inactivation of fatty acid 2-hydroxylase. Our findings provide important new insights into the molecular mechanisms responsible for neural pathogenesis caused by lipid metabolism abnormalities.-Kanetake, T., Sassa, T., Nojiri, K., Sawai, M., Hattori, S., Miyakawa, T., Kitamura, T., Kihara, A. Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.

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

“…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 . These correlations further support our hypothesis that decreases in 2‐OH GalCer are associated with the hypomyelination and spastic paraplegia observed in patients with the ELOVL1 mutation.…”

“…The balance beam test is a powerful analysis for identifying a subtle defect in motor function even in mice with no apparent spasticity or ambulation difficulty. 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.…”

“…In fact, we have previously identified similar defects in Aldh3a2-knockout mice using this test. 19 Aldh3a2-knockout mice serve as a model for Sjögren-Larsson syndrome, 31 an autosomal recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene and characterized by spastic paraplegia and ichthyosis 32 -symptoms also observed in patients with the ELOVL1 mutation. ALDH3A2 is a fatty aldehyde metabolizing enzyme, and Aldh3a2-knockout male 41 61 12 2 116 female 25 75 10 3 113 total 66 136 22 5 229 mice exhibit a decrease in 2-OH GalCer due to inactivation of FA2H, which synthesizes 2-OH FAs for 2-OH GalCer production.…”

“…All mice were 8 weeks old at the start of the behavioral testing. Behavioral tests were carried out using protocols identical to previous reports, except for the acoustic startle response test, in which mice were given acoustic stimuli with intensities of 70, 80, 85, 90, 95, 100, 105, 110, and 120 dB. Behavioral testing was performed between 09:00 and 18:00.…”

“…Eyes of 16 week‐old mice were fixed with SUPER FIX (Kurabo) at 4°C for >24 hours. They were then processed for dehydration, embedding in paraffin, preparation of 4 µm sections, deparaffinization, rehydration, and staining with hematoxylin and eosin using an automated staining system (Tissue Tek DRS 2000, Sakura Finetek) as described previously . Bright‐field images were captured using a Leica DM5000B microscope equipped with a DFC295 digital color camera (Leica Microsystems).…”