Mouse model for the complicated hereditary spastic paraplegias Troyer syndrome (SPG20)

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NINDS	CELLBIO-19

* FARE Award Winner

Authors

• B Renvoisé
• J Stadler
• R Singh
• JC Bakowska
• C Blackstone

Abstract

The hereditary spastic paraplegias (HSP) are a group of length-dependent distal axonopathy of corticospinal neurons. SPG20 gene, whose mutation results in a complicated HSP (Troyer syndrome), encodes Spartin protein. Spartin interacts selectively with the ESCRT-III protein Ist1 and inhibits BMP signaling. ESCRT-III proteins and BMP signaling play a crucial role in neuronal development. To characterize spartin functions in SPG20 pathogenesis, we created SPG20-/- knockout mice. Mice present a hind limb phenotype in old age associated with significant increase of axonal branches in primary cortical neuron cultures, suggesting that spartin is an inhibitor of branch formation. Analysis in embryonic fibroblast cells shows that the phosphorylation of Smad proteins, specific proteins of the BMP signaling pathway, is higher in SPG20-/- mice. As SPG20 patients also present short stature, we analyzed the bones and observed a significant increase in multinucleated cells in knee joint bones. Finally, we observed a defect in fat tissue, with a significant increase in lipid droplets (LD) and in the specific LD marker perilipin, supporting the idea that spartin plays an important role in LD formation. Taken together, our results show that SPG20-/- mouse is a useful model for studying key cellular pathogenic features of Troyer syndrome.

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