Defective myelination in mice harboring hypomyelinating leukodystrophy-associated HSPD1 mutation

Hypomyelinating leukodystrophy (HLD) is a genetic demyelinating and dismyelinating disease in the oligodendrocyte, the central nervous system (CNS) myelin-forming glia [1]. Pelizaeus-Merzbacher disease is a prototypic HLD and is now called HLD1. HLD1 is caused by mutations of the gene encoding proteolipid protein 1 (PLP1). HLD4 (OMIM No. 612233) is associated with a missense mutation of mitochondrial heat shock protein HSPD1 (also called Hsp60) [2]. HSPD1 is a member of the chaperonin ATPase family and participates in biosynthesis of a series of mitochondrial proteins involved in metabolic and redox regulation. We have reported that changes of protein properties caused by their diseasemutations are associatedwith their disease phenotypes of oligodendrocytes [3–7]. We herein report that transgenic mice expressing HLD4-associated (Asp-29-to-Gly) mutant of HSPD1 exhibit a defect in myelination in brain. We injected a DNA construct expressing HSPD1 (D29G) under the regulation of myelin-specific myelin basic protein (MBP) promoter [5] into ~200 of mouse fertilized eggs (Fig. S1), resulting in three lines of F0 generation's transgenicmice. The transgene of only one line was propagated into F1 and subsequent generations. We immunostained neonatal transgenic mouse brain tissues sliced along an anterior and posterior axis with an anti-MBP antibody. Transgenic mice exhibit decreased myelin formation in corpus callosum (line 1 in panels A and B of the Fig. 1) as well as other brain regions, comparing with littermate controls. Corpus callosum typically contains a lot of axons with myelin sheaths and is one of the major portions sufferingmyelin defects in human and rodents. Generatingmice exhibiting demyelinating or dismyelinating diseases may allow us not only to study how HLD-responsible gene mutations cause diseases but also to explore their therapeutic target molecules. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ymgmr.2017.03.003.