SPG42 HSP mechanism now well understood

Posted - February 2017 in Research Highlights

Study of mice confirms earlier findings

 

This Chinese study confirms the mechanism by which mutations in the SLC33A1 gene cause SPG42 type HSP. Mice with autosomal dominant SPG42 HSP, the same mode of inheritance as occurs in people, exhibited behavioural abnormalities and central neurodegeneration similar to humans.

 

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 Slc33a1S113R knock-in mice. Homozygous Slc33a1S113R mutant 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/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 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.

 

SOURCE: Dis Model Mech. 2017 Jan 1;10(1):53-62. doi: 10.1242/dmm.026880. Epub 2016 Nov 24. PMID: 27935820 PMCID: PMC5278525 [PubMed – in process] © 2017. Published by The Company of Biologists Ltd.

 

S113R mutation in SLC33A1 leads to neurodegeneration and augmented BMP signaling in a mouse model.

 

Liu P1, Jiang B1, Ma J1, Lin P2, Zhang Y1, Shao C1, Sun W3, Gong Y3.

 

1 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.

2 Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.

3 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China [email protected] [email protected]

Add your comment on this story