Mice with SPG31 have functions restored with treatment
The highly folded continuous membrane in cells known as the endoplasmic reticulum (ER) is vital to the normal functioning of cells through its role with multiple aspects of proteins. REEP1 modifies the shape of the ER and is involved in the ER stress response.
SPG31 mice, deficient in REEP1, show progressive motor impairment, impaired nerve function, increased ER stress, axonal degeneration and structural abnormalities. The mice were treated with a compound known to alleviate ER stress, which resulted in increased nerve and motor functions, showing the importance of maintaining balance in the ER and providing possibilities for treatment.
Hereditary 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.
SOURCE: Biol Open. 2020 Sep 29;9(9):bio054296. doi: 10.1242/bio.054296. PMID: 32878877 © 2020. Published by The Company of Biologists Ltd.
Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia
- State Key Laboratory of Membrane Biology, School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
- State Key Laboratory of Membrane Biology, School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China [email protected]