title: Spg20-/- mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling.
abstract: Hereditary spastic paraplegias (HSPs; SPG1-48) are inherited neurological disorders characterized by lower extremity spasticity and weakness. Loss-of-function mutations in the SPG20 gene encoding spartin cause autosomal recessive Troyer syndrome (SPG20), which has additional features of short stature, cognitive deficits and distal amyotrophy. To identify cellular impairments underlying Troyer syndrome, we generated Spg20-/- mice, which exhibit progressive gait defects. Although gross central nervous system pathology appeared largely normal, cerebral cortical neurons cultured from neonatal Spg20-/- mice exhibited increased axon branching, a phenotype suppressed by reintroducing spartin and which required its interaction with the endosomal sorting complex required for transport (ESCRT)-III protein IST1. Analysis of the bone morphogenetic protein (BMP) signaling pathway in Spg20-/- embryonic fibroblasts indicated that Smad1/5 phosphorylation is modestly elevated, possibly due to alterations in BMP receptor trafficking. Cytokinesis was impaired in embryonic fibroblasts cultured from Spg20-/- mice, and binucleated chondrocytes were prominent in epiphyseal growth plates of bones in Spg20-/- mice, perhaps explaining the short stature of patients. Finally, adipose tissue from Spg20-/- female mice exhibited increased lipid droplet (LD) numbers and alterations in perilipin levels, supporting a role for spartin in LD maintenance. Taken together, our results support multimodal functions for spartin that provide important insights into HSP pathogenesis.
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Benoît
authors.initials: B
authors.lastname: Renvoisé
authors.forename: Julia
authors.initials: J
authors.lastname: Stadler
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Bakowska
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D048749:Cytokinesis / Q000235:genetics; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005684:Gait / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000070778:Perilipin-1; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008055:Lipids; D000070778:Perilipin-1; D010750:Phosphoproteins; C562344:SPG20 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse