Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany; Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France.
Neurobiol Dis. 2021 Apr;151:105256. doi: 10.1016/j.nbd.2021.105256. Epub 2021 Jan 8.
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Using H4, SH-SY5Y and HEK293 cells, we found that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found that doxycycline induces a cellular redistribution of aggregates in a C.elegans animal model of PD, an effect that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.
帕金森病（PD）和路易体痴呆（DLB）是神经退行性疾病，其特征是α-突触核蛋白（aSyn）的错误折叠和聚集。多西环素是一种四环抗生素，具有神经保护作用，最初被认为是由于其抗炎特性。最近，人们提出了多西环素发挥神经保护作用的另一种机制，因为已经表明它可以抑制淀粉样蛋白聚集。在这里，我们使用实时震颤诱导转化（RT-QuiC）在体内、体外和无细胞系统中研究了多西环素对 aSyn 聚集的影响。使用 H4、SH-SY5Y 和 HEK293 细胞，我们发现多西环素减少了细胞中 aSyn 聚集的数量和大小。此外，多西环素抑制重组 aSyn 的聚集和种子形成，并减轻线粒体衍生的活性氧的产生。最后，我们发现多西环素在 PD 的 C. elegans 动物模型中诱导细胞内聚集物的重新分布，这种效应与多巴胺能功能的恢复有关。总之，我们提供了强有力的证据表明，多西环素治疗可能是对抗突触核蛋白病的有效策略。
