Impaired cell structure connected with symptoms
SPG 31 mice displayed a gait disorder closely resembling SPG 31 in humans. Affected mouse nerve cells had impaired cell structure with implications for long-term function and survival.
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.
SOURCE: J Clin Invest. 2013 Oct 1;123(10):4273-82. doi: 10.1172/JCI65665. Epub 2013 Sep 24. PMID: 24051375 [PubMed – in process] PMCID: PMC3784524
A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.
Beetz C, Koch N, Khundadze M, Zimmer G, Nietzsche S, Hertel N, Huebner AK, Mumtaz R, Schweizer M, Dirren E, Karle KN, Irintchev A, Alvarez V, Redies C, Westermann M, Kurth I, Deufel T, Kessels MM, Qualmann B, Hübner CA.