title: Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.
abstract: Hereditary spastic paraplegias (HSPs; SPG1-76 plus others) are length-dependent disorders affecting long corticospinal axons, and the most common autosomal dominant forms are caused by mutations in genes that encode the spastin (SPG4), atlastin-1 (SPG3A) and REEP1 (SPG31) proteins. These proteins bind one another and shape the tubular endoplasmic reticulum (ER) network throughout cells. They also are involved in lipid droplet formation, enlargement, or both in cells, though mechanisms remain unclear. Here we have identified evidence of partial lipoatrophy in Reep1 null mice in addition to prominent spastic paraparesis. Furthermore, Reep1-/- embryonic fibroblasts and neurons in the cerebral cortex both show lipid droplet abnormalities. The apparent partial lipodystrophy in Reep1 null mice, although less severe, is reminiscent of the lipoatrophy phenotype observed in the most common form of autosomal recessive lipodystrophy, Berardinelli-Seip congenital lipodystrophy. Berardinelli-Seip lipodystrophy is caused by autosomal recessive mutations in the BSCL2 gene that encodes an ER protein, seipin, that is also mutated in the autosomal dominant HSP SPG17 (Silver syndrome). Furthermore, REEP1 co-immunoprecipitates with seipin in cells. This strengthens the link between alterations in ER morphogenesis and lipid abnormalities, with important pathogenic implications for the most common forms of HSP.
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Benoît
authors.initials: B
authors.lastname: Renvoisé
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Brianna
authors.initials: B
authors.lastname: Malone
authors.affiliation: Developmental Neurobiology Section.
authors.forename: Melanie
authors.initials: M
authors.lastname: Falgairolle
authors.affiliation: Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jeeva
authors.initials: J
authors.lastname: Munasinghe
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Julia
authors.initials: J
authors.lastname: Stadler
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sibilla
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Seong H
authors.initials: SH
authors.lastname: Park
authors.affiliation: Cell Biology Section, Neurogenetics Branch.
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics*; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism / Q000473:pathology; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D026901:Membrane Transport Proteins; C495318:REEP1 protein, human; D020962:Heterotrimeric GTP-Binding Proteins