Abstract
ABSTRACTHereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases. HSPs are characterized by lower-extremity weakness and spasticity. However, there is no specific clinical treatment strategy to prevent or reverse nerve degeneration in HSPs. Mutations in receptor expression-enhancing protein 1 (REEP1) are well-recognized and relatively common causes of autosomal dominant HSPs. REEP1 modifies the endoplasmic reticulum (ER) shape, and is implicated in the ER stress response. Defects in the ER stress response seem to be crucial mechanisms underlying HSP neurodegeneration. Here, we report that REEP1−/− mice exhibit progressive motor deficits, along with denervation of neuromuscular junctions and increased ER stress. Moreover, marked axonal degeneration and morphological abnormalities are observed. In this study, we treated both REEP1−/− and wild-type (WT) mice with salubrinal, which is a specific inhibitor of ER stress, and we observed increased nerve-muscle connections and enhanced motor functions. Our data highlight the importance of ER homeostasis in HSPs, providing new opportunities for HSP treatment.
Highlights
Hereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases with a prevalence of ∼1.3–9.6 in 100,000 individuals (Guglielmi, 2020)
The results demonstrated that axonal degeneration of the spinal cord motor neurons in receptor expression-enhancing protein 1 (REEP1)−/− mice led to the reduced innervation of these muscles, which further caused the loss of muscular force in REEP1−/− mice
It is of great value to more deeply investigate the underlying functions of the REEP1 gene and the mechanisms underlying autosomal dominant HSPs to identify new treatment strategies for this disease
Summary
Hereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases with a prevalence of ∼1.3–9.6 in 100,000 individuals (Guglielmi, 2020). More than 70 distinct genetic loci have been implicated in HSPs (Lim et al, 2015). Most types of HSPs are designated by their genetic loci (Spastic paraplegia, SPG1-78), which are numbered in order of their discovery (Blackstone, 2018; Fink, 2013; de Souza et al, 2017; Guglielmi, 2020). Autosomal dominant HSPs are the most common type and found in 75–80% of patients. Most cases (∼50%) of HSPs result from autosomal dominant mutations of just three genes: SPG3A/ATL1, State Key Laboratory of Membrane Biology, School of Life Sciences, PKU-IDG/ McGovern Institute for Brain Research, Peking University, Beijing 100871, China
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