L2hgdh Deficiency 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 generated L2hgdh knockout (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. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.

KEYWORDS:

• L2HGDH
• 2-HG
• leukoencephalopathy
• gliosis
• neurodegeneration

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Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00492-16.

ACKNOWLEDGMENTS

We thank members of the Fudan MCB laboratory for their valuable inputs and support throughout this study and Jian Hu, Yuan Zhu, and Vivian Fu for critical discussion and reading of the manuscript.

This work was supported by the CAS Strategic Priority Research Program (XDB02050400), NSFC grants (91432111) to Z.Q, by the 973 Program (no. 2012CB910303 to D.Y. and no. 2012CB910101 to K.-L.G.), the NSFC grant (no. 81372198 and no. 81522033 to D.Y.), the NSFC Program of International Cooperation and Exchanges (no. 81120108016 to Y.X.), and the Shanghai “Phosphor” Science Foundation, China (no. 14QA1400600 to D.Y.). This work was also supported by NIH grants (GM067113 and CA1638311 to Y.X.; CA196878 and GM51586 to K.-L.G.).