JCI: 痉挛基因reticulon2导致神经细胞变性

Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison,Carla Babalini, Michela D'Aloia, Pasqua Montieri, Rebecca Schüle, Hiroyuki Ishiura,Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon,Tine Deconinck, Jia Huang, Giorgio Bernardi, Jeffery M. Vance, Mark T. Rogers,Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Sch?ls, Antonio Orlacchio, Evan Reid and Stephan Züchner

Abstract: Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12).

These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly trunc-ated protein. Wild-type reticulon 2, but not the trunc-ated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.