Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity.
Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity.
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DOI：
10.1371/journal.pbio.1002583
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发表时间：
2016-12
期刊：
影响因子：
9.8
通讯作者：
Noble M
中科院分区：
文献类型：
--
作者：
Folts CJ;Scott-Hewitt N;Pröschel C;Mayer-Pröschel M;Noble M
神经退行性溶酶体储存障碍(LSD)是一种严重的无法治疗的疾病，其潜在的细胞功能障碍机制尚不清楚。我们发现，与三种不同LSD相关的有毒脂类扰乱了多种溶酶体和其他细胞功能。无偏见的药物发现揭示了几种结构上不同的保护性化合物，被批准用于其他用途，以防止这些脂类的溶酶体和细胞毒性。有毒的脂类和保护剂在控制溶酶体的pH和作为毒性和保护的关键成分的再酸化方面表现出意外的趋同。在抽动小鼠(Krabbe病[KD]的模型)中，一种中枢神经系统(CNS)穿透性保护剂拯救了髓鞘和少突胶质细胞(OL)祖细胞，改善了运动行为，延长了寿命。我们的研究揭示了与几种LSD相关的共同原则，其中不同的细胞和生化破坏似乎是次要的，因为特定的脂类破坏了溶酶体的pH调节。这些研究还提供了新的保护性策略，在严重LSD的小鼠模型中提供了治疗益处。来自三种不同基因的溶酶体储存障碍的不同结构相关的脂类足以导致多种功能障碍，这些功能障碍汇聚在溶酶体pH的破坏作为核心致病机制。神经退行性溶酶体储存障碍(LSD)是一种严重的、不可治疗的隐性遗传疾病，会对神经系统造成毁灭性的损害。这些疾病表现出严重的溶酶体(分解脂质和蛋白质的细胞器)和细胞功能的其他方面的破坏。然而，突变导致这些功能障碍的方式还知之甚少。通过研究三种不同LSD中积累的不同脂类，我们发现具有特定共同结构的脂类足以引起多种溶酶体和细胞功能障碍，包括溶酶体pH的异常碱化。我们通过促进溶酶体的再酸化防止了所有这些功能障碍，并发现了几种药物--已经被批准用于其他目的--具有恢复溶酶体pH和拯救细胞的意想不到的能力。在严重LSD的遗传小鼠模型中，这些化合物之一减少了组织损伤，改善了生活质量，并延长了生存时间。与之前关于个体疾病的研究不同，我们的研究提供了与几种LSD相关的新的共同原则，并发现了能够在体内疾病相关模型中提供多种益处的相关化合物。
Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD. Different structurally related lipids from three genetically distinct lysosomal storage disorders are sufficient to cause multiple dysfunctions that converge on disruption of lysosomal pH as a core pathogenic mechanism. Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable recessive genetic disorders that cause devastating damage to the nervous system. These diseases exhibit severe disruption of lysosomes (a cellular organelle that breaks down lipids and proteins) and other aspects of cell function. However, the means by which mutations cause these dysfunctions are poorly understood. By studying different lipids that accumulate in three different LSDs, we found that lipids with specific shared structures are sufficient to cause multiple lysosomal and cellular dysfunctions, including an abnormal alkalization of the lysosomal pH. We prevented all of these dysfunctions by promoting lysosomal re-acidification and discovered several drugs—already approved for other purposes—with unexpected abilities to restore lysosomal pH and rescue cells. In a genetic mouse model of a severe LSD, one of these compounds decreased tissue damage, improved quality of life, and extended survival. In contrast with previous studies on individual disorders, our study provides novel shared principles relevant to several LSDs and uncovers relevant compounds able to provide multiple benefits in a disease-relevant model in vivo.
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影响因子：
5.3
作者：
Cantuti-Castelvetri, Ludovico;Maravilla, Erick;Bongarzone, Ernesto R.
通讯作者：
Bongarzone, Ernesto R.
影响因子：
6.1
作者：
Cantuti-Castelvetri, Ludovico;Zhu, Hongling;Givogri, Maria I.;Chidavaenzi, Robstein L.;Lopez-Rosas, Aurora;Bongarzone, Ernesto R.
通讯作者：
Bongarzone, Ernesto R.
影响因子：
3.3
作者：
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通讯作者：
Mitchell CH
影响因子：
4.7
作者：
Bibollet-Bahena, Olivia;Almazan, Guillermina
通讯作者：
Almazan, Guillermina
影响因子：
3.3
作者：
Barriere, Herve;Bagdany, Miklos;Lukacs, Gergely L.
通讯作者：
Lukacs, Gergely L.