Institute for Immunology and School of Basic Medicine, Tsinghua University, Beijing 100084, China.
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Protein Cell. 2024 Nov 1;15(11):818-839. doi: 10.1093/procel/pwae016.
Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease and Parkinson's disease. Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.
清道夫受体 B 类成员 2（SCARB2）与戈谢病和帕金森病有关。SCARB2 基因的缺失会导致进行性肌阵挛性癫痫（PME），这是一组罕见的遗传性神经退行性疾病，其特征是肌阵挛。我们发现，小鼠 Scarb2 基因的缺失会导致年龄依赖性的膳食脂质吸收不良，同时伴有维生素 E 缺乏。我们的研究表明，Scarb2 基因的缺失与肠道菌群失调和胆汁酸池改变有关，导致 FXR 在肠道中过度激活。FXR 的过度激活会损害上皮细胞的更新和脂质吸收。携带 SCARB2 突变的患者维生素 E 水平严重降低，无法吸收膳食中的维生素 E。最后，抑制 FXR 或补充维生素 E 可改善 Scarb2 基因敲除小鼠的神经运动障碍和神经病变。这些数据表明，胃肠道功能障碍与 SCARB2 缺乏相关的神经退行性变有关，通过解决营养缺乏和胃肠道问题可以改善 SCARB2 相关的神经退行性变。
