Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
Department of Neuroscience and Rehabilitation, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24). doi: 10.1073/pnas.2020078118.
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.
多发性硬化症（MS）是一种神经炎症和神经退行性疾病，其特征是髓鞘损伤后轴突最终神经元丢失。MS 的病因和病理生理学仍然难以捉摸，目前尚无完全有效的治疗方法。我们研究了自噬（生理上是一种控制细胞成分降解的细胞内途径）和线粒体自噬（一种去除功能失调线粒体的特定形式的自噬）在 MS 中的作用。我们发现，在疾病活动期，MS 患者的生物流体中的自噬和线粒体自噬标志物水平显著升高，表明这些过程被激活。与这一观点一致的是，体外和体内 MS 模型（由促炎细胞因子、溶血卵磷脂和铜吡咯啉诱导）与线粒体活性严重受损有关，导致乳酸代谢并促使自噬通量和线粒体自噬增加。多种结构和机制上不相关的自噬抑制剂可改善髓鞘生成并使轴突髓鞘正常化，两种此类抑制剂，即广泛使用的抗精神病药物氟哌啶醇和氯氮平，也可显著改善铜吡咯啉诱导的运动障碍。这些数据表明自噬在 MS 中起因果作用；其抑制在疾病的实验模型中强烈减弱行为迹象。因此，氟哌啶醇和氯氮平可能是治疗 MS 的另一种治疗工具。
