A spastic paraplegia mouse model reveals REEP1-dependent ER shaping
Christian Beetz, … , Britta Qualmann, Christian A. Hübner
Christian Beetz, … , Britta Qualmann, Christian A. Hübner
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4273-4282. https://doi.org/10.1172/JCI65665.
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Research Article

A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

Abstract

Axonopathies 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.

Authors

Christian Beetz, Nicole Koch, Mukhran Khundadze, Geraldine Zimmer, Sandor Nietzsche, Nicole Hertel, Antje-Kathrin Huebner, Rizwan Mumtaz, Michaela Schweizer, Elisabeth Dirren, Kathrin N. Karle, Andrey Irintchev, Victoria Alvarez, Christoph Redies, Martin Westermann, Ingo Kurth, Thomas Deufel, Michael M. Kessels, Britta Qualmann, Christian A. Hübner

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Figure 6

REEP1 deficiency results in a dose-dependent reduction of the complexity of the peripheral ER but not of the nuclear envelope in neurons in the primary motor cortex.

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REEP1 deficiency results in a dose-dependent reduction of the complexity...
(A) Representative TEM images of neuronal somata in the primary motor cortex of Reep+/+ and Reep1–/– mice. The cytoplasm is colored in yellow, the nucleus in blue, and the ER in red. Scale bars: 2 μm for whole-cell images and 400 nm for insets. (B–G) Quantitative evaluations (mean ± SEM) of nuclear envelope and peripheral ER parameters in TEM sections of neuronal somata in the primary motor cortex of Reep1+/+, Reep1+/–, and Reep1–/– mice (4 animals per genotype, 12 cells per animal). Neither the length of the nuclear envelope (B), its sphericity (C), nor the number of nuclear pockets observed per cell section (D) differed between genotypes. Although the sum of the length of all peripheral ER structures per cell section was unaltered (E), a REEP1 dose–dependent increase was observed in the average length of individual ER structures (F) associated with a decrease in the number of individual ER structures per cell section (G). *P < 0.05 (one-way ANOVA).