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首页> 外文期刊>BMC Neuroscience >Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis
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Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis

机译：在青少年神经元类脑脂质脂褐变的小脑细胞模型中，膜运输和线粒体异常先于亚基c沉积

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Background JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a ~1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3 Δex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. Results To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized Cb Cln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous Cb Cln3 Δex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. Conclusions These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival.
机译：背景JNCL是一种隐性遗传的儿童期神经退行性疾病，通常由〜1 kb CLN3突变引起。导致的板条蛋白活性丧失导致线粒体ATP合酶，c亚基的沉积和中枢神经系统神经元的特异性丧失。我们以前曾产生过Cln3 Δex7/ 8 敲入小鼠，它们复制了常见的JNCL突变，表达了突变的板条蛋白并表现出JNCL样的病理。结果为了阐明神经元细胞中常见JNCL突变的后果，我们使用P4敲入小鼠小脑建立有条件永生化的Cb Cln3野生型，杂合和纯合神经元前体细胞系，可以将其分化为MAP-2和NeuN阳性神经元样细胞。纯合Cb Cln3 Δex7/ 8 前体细胞表达低水平的突变巴丁蛋白，并且在融合时老化时会积累ATPase亚基c。在亚汇合生长时也观察到隐性表型。组织蛋白酶D的运输和加工发生了变化，尽管酶活性没有受到明显影响，溶酶体的大小和分布也发生了变化，并且内吞作用减少了。另外，线粒体异常延长，细胞ATP水平降低，氧化应激后的存活期降低。结论这些发现表明，巴丁汀是细胞内膜运输和线粒体功能所必需的。此外，这些缺陷可能是JNCL疾病过程中的早期事件，并且可能特别影响神经元的存活。

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