Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX, 78712, USA.
Sci Rep. 2022 Dec 1;12(1):20753. doi: 10.1038/s41598-022-24537-3.
The sigma 2 receptor (σR) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σR/TMEM97 binding compounds are neuroprotective, suggesting a role of σR/TMEM97 in neurodegenerative processes. To understand the function of σR/TMEM97 in neurodegeneration pathways, we characterized ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97 mice and found that RGCs in TMEM97 mice are resistant to degeneration. In addition, intravitreal injection of a selective σR/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σR/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σR/TMEM97 is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σR/TMEM97 in RGCs and likely in other σR/TMEM97 expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches for RGC degenerative diseases by inhibiting σR/TMEM97.
σ2 受体（σR）最近被鉴定为一种内质网（ER）膜蛋白，称为跨膜蛋白 97（TMEM97）。研究表明，σR/TMEM97 结合化合物具有神经保护作用，提示 σR/TMEM97 在神经退行性过程中起作用。为了了解 σR/TMEM97 在神经退行性通路中的功能，我们对 TMEM97 小鼠的缺血诱导的视网膜神经节细胞（RGC）变性进行了表征，发现 TMEM97 小鼠的 RGC 对变性具有抗性。此外，选择性 σR/TMEM97 配体 DKR-1677 的玻璃体内注射可显著保护野生型小鼠的 RGC 免受缺血诱导的变性。我们的结果提供了确凿的证据，证明 σR/TMEM97 在缺血性损伤后促进 RGC 死亡，抑制 σR/TMEM97 的功能具有神经保护作用。这项工作是阐明 σR/TMEM97 在 RGC 中的生物学和功能的突破，并且可能在其他表达 σR/TMEM97 的神经元中也是如此。此外，这些发现支持未来通过抑制 σR/TMEM97 来开发针对 RGC 退行性疾病的新神经保护方法的研究。
