TY - JOUR
T1 - Neural symptoms in a gene knockout mouse model of Sjogren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide
AU - Kanetake, Tsukasa
AU - Sassa, Takayuki
AU - Nojiri, Koki
AU - Sawai, Megumi
AU - Hattori, Satoko
AU - Miyakawa, Tsuyoshi
AU - Kitamura, Takuya
AU - Kihara, Akio
N1 - Funding Information:
The authors thank Dr. T. Naganuma and S. Takagi (both from Hokkaido University) for breeding the mice, preparing the eye samples, and helpful discussion; Dr. R. A. Zoeller (Boston University School of Medicine, Boston MA, USA) for providing FAA-K1A cells. The authors owe thanks for the use of the mass spectrometer received from Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), which is funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan under the “Support Program for Implementation of a New Equipment Sharing System,” and from the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from MEXT and the Japan Agency for Medical Research and Development (AMED). This work was supported by funding from the Ono Medical Research Foundation, by the Advanced Research and Development Programs for Medical Innovation (AMED–CREST) Grant JP18gm0910002 (AMED), by a Grant-in-Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” from MEXT, and by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) Grants JP18H03976 and JP18H04664 (to A.K.) and JP16K08220 (to T.S.). Behavioral analyses were performed at the Institute for Comprehensive Medical Science, Fujita Health University (Joint Usage/Research Center for Genes, Brain and Behavior, accredited by MEXT). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2019/1
Y1 - 2019/1
N2 - Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjogren-Larsson syndrome (SLS) i s 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 neuronsinthemouse brain, and neurons of Aldh3a2knockout (KO)mice exhibitedimpaired metabolism ofthelongchain 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.
AB - Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjogren-Larsson syndrome (SLS) i s 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 neuronsinthemouse brain, and neurons of Aldh3a2knockout (KO)mice exhibitedimpaired metabolism ofthelongchain 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.
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U2 - 10.1096/fj.201800291R
DO - 10.1096/fj.201800291R
M3 - Article
C2 - 30085884
AN - SCOPUS:85059241498
VL - 33
SP - 928
EP - 941
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 1
ER -