title: S113R mutation in SLC33A1 leads to neurodegeneration and augmented BMP signaling in a mouse model.
abstract: The S113R mutation (c.339T>G) (MIM #603690.0001) in SLC33A1 (MIM #603690), an ER membrane acetyl-CoA transporter, has been previously identified in individuals with hereditary spastic paraplegia type 42 (SPG42; MIM #612539). SLC33A1 has also been shown to inhibit the bone morphogenetic protein (BMP) signaling pathway in zebrafish. To better understand the function of SLC33A1, we generated and characterized Slc33a1S113Rknock-in mice. Homozygous Slc33a1S113Rmutant mice were embryonic lethal, whereas heterozygous Slc33a1 mutant mice (Slc33a1wt/mut) exhibited behavioral abnormalities and central neurodegeneration, which is consistent with hereditary spastic paraplegia (HSP) phenotypes. Importantly, we found an upregulation of BMP signaling in the nervous system and mouse embryonic fibroblasts of Slc33a1wt/mutmice. Using a sciatic nerve crush injury model in vivo and dorsal root ganglion (DRG) culture in vitro we showed that injury-induced axonal regeneration in Slc33a1wt/mutmice was accelerated and mediated by upregulated BMP signaling. Exogenous addition of BMP signaling antagonist, noggin, could efficiently alleviate the accelerated injury-induced axonal regrowth. These results indicate that SLC33A1 can negatively regulate BMP signaling in mice, further supporting the notion that upregulation of BMP signaling is a common mechanism of a subset of hereditary spastic paraplegias.
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Pingting
authors.initials: P
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yinshuai
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China sunwenjie@sdu.edu.cn yxg8@sdu.edu.cn.
authors.forename: Wenjie
authors.identifier: 0000-0001-7399-1712
authors.initials: W
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China sunwenjie@sdu.edu.cn yxg8@sdu.edu.cn.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006720:Homozygote; D026901:Membrane Transport Proteins / Q000235:genetics*; D009043:Motor Activity; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009416:Nerve Regeneration; D010641:Phenotype; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D019485:Bone Morphogenetic Proteins; D026901:Membrane Transport Proteins; C105440:Slc33a1 protein, mouse
keywords: Bone morphogenetic protein (BMP); Hereditary spastic paraplegia; Knock-in mouse model; Neurodegeneration; SLC33A1