Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases
Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases
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DOI：
10.1080/15548627.2015.1136769
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Dehay, Benjamin
中科院分区：
文献类型：
--
作者：
Bourdenx, Mathieu;Daniel, Jonathan;Dehay, Benjamin
溶酶体损伤导致溶酶体贮积障碍（LSD），并参与神经退行性疾病的发病机制，特别是帕金森病（PD）。因此，增强或恢复溶酶体介导的降解的策略似乎是诱人的疾病改善疗法。在这里，我们证明了聚乳酸-羟基乙酸酯（PLGA）酸性纳米颗粒（aNP）在一系列PD的毒素和遗传细胞模型中，即atp13a2突变或耗尽细胞或葡萄糖脑苷酶（GBA）突变细胞，以及溶酶体相关肌病的遗传模型中，可以恢复受损的溶酶体功能。我们发现PLGA-aNP在24小时内被转运到溶酶体，降低了溶酶体的pH值，挽救了氯喹（chloroquine， CQ）诱导的毒性。PLGA-aNP治疗后缺陷溶酶体的再酸化可恢复不同病理背景下溶酶体的功能。最后，我们的研究结果表明，PLGA-aNP可能在神经元脑内注射后检测到，并通过损害溶酶体的救援机制减轻体内pd相关的神经退行性变。
Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomal-mediated degradation thus appear as tantalizing disease-modifying therapeutics. Here we demonstrate that poly(DL-lactide-co-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration in vivo by mechanisms involving a rescue of compromised lysosomes.