Bové Jordi, Martínez-Vicente Marta, Dehay Benjamin, Perier Celine, Recasens Ariadna, Bombrun Agnes, Antonsson Bruno, Vila Miquel
Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
Merck Serono S.A.; Geneva Research Center; Geneva, Switzerland.
Autophagy. 2014 May;10(5):889-900. doi: 10.4161/auto.28286. Epub 2014 Mar 26.
Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.
溶酶体破坏日益被视为帕金森病（PD）中的一个主要致病事件。在源自PD的样本中观察到神经元内溶酶体数量减少、溶酶体相关蛋白水平降低以及未降解自噬体（AP）的积累，这些样本包括成纤维细胞、诱导多能干细胞衍生的多巴胺能神经元和死后脑组织。对有毒和遗传性啮齿动物PD模型的机制研究将与PD相关的溶酶体破裂归因于溶酶体膜通透性异常（LMP）。然而，与PD相关的LMP及随后溶酶体缺陷的分子机制实际上仍不清楚，因此无法对其进行潜在的治疗靶向。在此我们表明，促凋亡蛋白BAX（BCL2相关X蛋白）在PD模型中使线粒体膜通透性增加并在PD患者中被激活，在用帕金森神经毒素MPTP处理后，在体外和体内均在与LMP、溶酶体破坏、自噬体积累相关的时间范围内，以及在线粒体通透性增加和多巴胺能神经变性之前，早期转位并内化到溶酶体膜中。支持BAX对溶酶体膜有直接通透作用的是，重组BAX能够在纯化的小鼠脑溶酶体中诱导LMP，并且后者可通过药理学阻断BAX通道活性来预防。此外，药理学上抑制BAX通道能够预防LMP、恢复溶酶体水平、逆转AP积累，并减轻MPTP在体外和体内引起的线粒体通透性增加和整体黑质纹状体变性。总体而言，我们的结果表明，与PD相关的溶酶体损伤依赖于BAX诱导的LMP，并指出能够阻断BAX通道活性的小分子可能有助于减轻PD中发生的溶酶体缺陷和神经变性。
