Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, 90095, USA.
School of Nursing, University of California, Los Angeles, CA, 90095, USA.
Mol Brain. 2021 Apr 19;14(1):70. doi: 10.1186/s13041-021-00776-9.
We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model.
The acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined.
RESULTS/DISCUSSION: In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.
我们之前曾报道过，坎比诺尔（DDL-112）是一种已知的中性鞘磷脂酶 2（nSMase2）抑制剂，可在体外细胞模型中抑制细胞外囊泡（EV）/外泌体的产生，并减少 tau 种子的传播。nSMase2 酶参与携带致病蛋白种子的外泌体的产生，并可能有助于与帕金森病（PD）等神经退行性疾病相关的病理蛋白聚集的细胞间传播。在这里，我们进行了体内研究，以确定 DDL-112 是否可以减少 PD 小鼠模型中大脑 EV/外泌体的产生和致病的α突触核蛋白（αSyn）的传播。
研究了单次给予 DDL-112 对 Thyl-αSyn PD 模型小鼠脑内白细胞介素-1β诱导的细胞外囊泡（EV）释放的急性影响，以及 DDL-112 连续 5 周给药对 PD 模型的行为/运动功能和蛋白水解酶抗性 αSyn 聚集的慢性影响。
结果/讨论：在急性研究中，DDL-112 的预处理可减少 EV/外泌体的生物发生，而在慢性研究中，DDL-112 的治疗与黑质中αSyn 聚集的减少和运动功能的改善相关。因此，抑制 nSMase2 为神经退行性疾病的治疗发展提供了一种新方法，有可能减少疾病特异性致病蛋白的传播。
