title: L2hgdhDeficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration.
abstract: l-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generatedL2hgdhknockout (KO) mice and observed a robust increase of l-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues.L2hgdhKO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover,L2hgdhdeficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data providein vivoevidence thatL2hgdhmutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ma
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Renqiang
authors.initials: R
authors.lastname: Sun
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|China Novartis Institutes for BioMedical Research Co. Ltd., Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, SJTU-SM, Shanghai, China.
authors.forename: Wanglong
authors.initials: W
authors.lastname: Deng
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai, China.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: He
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai, China.
authors.forename: Minbiao
authors.initials: M
authors.lastname: Ji
authors.affiliation: China Novartis Institutes for BioMedical Research Co. Ltd., Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Institute of Neuroscience, Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China zqiu@ion.ac.cn yedan@fudan.edu.cn.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China zqiu@ion.ac.cn yedan@fudan.edu.cn.|Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000429:Alcohol Oxidoreductases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D001284:Atrophy; D001835:Body Weight; D003711:Demyelinating Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005911:Gliosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D005977:Glutarates / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D056784:Leukoencephalopathies / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D055495:Neurogenesis; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D013737:Testis / Q000473:pathology; D066127:White Matter / Q000002:abnormalities / Q000473:pathology
chemical_list: D005977:Glutarates; D006657:Histones; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase; D008239:Lysine
keywords: 2-HG; L2HGDH; gliosis; leukoencephalopathy; neurodegeneration