Beetz, C.Koch, N.Khundadze, M.Zimmer, G.Nietzsche, S.Hertel, N.Huebner, AKMumtaz, R.Schweizer, M.Dirren, Elisabeth AnneKarle, KNIrintchev, A.Alvarez, V.Redies, C.Westermann, M.Kurth, I.Deufel, T.Kessels, MMQualmann, B.Hübner, CA2013-12-022013-12-022013-12-02201310.1172/JCI65665https://infoscience.epfl.ch/handle/20.500.14299/97395WOS:000325443100023Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.text::journal::journal article::research article