Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis.
Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis.
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DOI：
10.1186/1471-2202-5-57
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发表时间：
2004-12-10
期刊：
影响因子：
2.4
通讯作者：
Cotman SL
中科院分区：
文献类型：
--
作者：
Fossale E;Wolf P;Espinola JA;Lubicz-Nawrocka T;Teed AM;Gao H;Rigamonti D;Cattaneo E;MacDonald ME;Cotman SL
JNCL是一种隐性遗传的，儿童期发病的神经退行性疾病，最常见的原因是约1 kb的CLN3突变。由此导致的蛋白活性丧失导致线粒体ATP合成酶亚基c的沉积和中枢神经系统神经元的特异性丧失。我们之前产生了Cln3Δex7/8敲入小鼠，它们复制了常见的JNCL突变，表达突变的battenin并表现出JNCL样病理。为了阐明常见的JNCL突变对神经元细胞的影响，我们使用P4敲入小鼠小脑建立了条件永生化的CbCln3野生型、杂合型和纯合型神经元前体细胞，这些细胞可以分化为MAP-2和neun阳性的神经元样细胞。纯合子CbCln3Δex7/8前体细胞表达低水平的突变蛋白，并在融合老化时积累atp酶亚基c。在亚融合生长时也观察到隐性表型；组织蛋白酶D的运输和加工被改变，尽管酶活性没有显著影响，溶酶体的大小和分布被改变，内吞作用减少。此外，线粒体异常拉长，细胞ATP水平降低，氧化应激后的存活率降低。这些发现表明，筋蛋白是细胞膜内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，可能特别影响神经元存活。
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 Cln3Δex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Δex7/8 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. 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.
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影响因子：
3.5
作者：
Cotman, SL;Vrbanac, V;MacDonald, ME
通讯作者：
MacDonald, ME
影响因子：
5.3
作者：
JAT, PS;CEPKO, CL;SHARP, PA
通讯作者：
SHARP, PA
影响因子：
4.1
作者：
Partanen, S;Storch, S;Braulke, T
通讯作者：
Braulke, T
DOI：
10.1073/pnas.2136651100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Kim, Y;Ramirez-Montealegre, D;Pearce, DA
通讯作者：
Pearce, DA
影响因子：
3.3
作者：
Kyttälä, A;Ihrke, G;Luzio, JP
通讯作者：
Luzio, JP