S113R mutation in Slc33a1 leads to neurodegeneration and augmented BMP signaling in a mouse model

The S113R mutation (c.339T>G) (MIM #603690.0001) in SLC33A1 (MIM #603690), an ER membrane acetyl-CoA transporter, has been previously identified in patients with hereditary spastic paraplegia type 42 (SPG42; MIM #612539). SLC33A1 has also been shown to inhibit bone morphogenetic protein (BMP) signaling pathway in zebrafish. To better understand the function of SLC33A1, we generated and characterized Slc33a1S113R knock-in mice. Homozygous Slc33a1S113R mutant mice were embryonic lethal, while heterozygous Slc33a1 mutant mice (Slc33a1wt/mut) exhibited behavioral abnormalities and central neurodegeneration, which is consistent with HSP phenotypes. Importantly, we found an upregulation of BMP signaling in the nervous system and mouse embryonic fibroblasts of Slc33a1wt/mut mice. 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/mut mice was accelerated and was 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.