Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis.
Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis.
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DOI：
10.1371/journal.pone.0035493
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Galliciotti G
中科院分区：
文献类型：
--
作者：
Thelen M;Damme M;Schweizer M;Hagel C;Wong AM;Cooper JD;Braulke T;Galliciotti G
变异性婴儿晚期神经元蜡样脂褐质沉积症是一种致命的溶酶体储存疾病，伴有脑中局部萎缩和明显的神经元丢失，由CLN 6基因突变引起。CLN 6是一种功能未知的非糖基化内质网（ER）驻留膜蛋白。为了研究导致CLN 6疾病中神经变性的机制，我们检查了nclf小鼠，一种天然存在的人类CLN 6疾病模型。在小脑浦肯野细胞、丘脑、海马、嗅球和皮质II至V层中发现了显着的自发荧光和电子致密溶酶体储存物质。nclf发病机制的另一个显着早期特征是局部星形细胞增多症，这在许多大脑区域和更广泛的小胶质细胞增生中很明显。在nclf小鼠中发现的突变Cln 6的表达分析证明了具有减少的半衰期的截短蛋白的合成。而快速降解的突变Cln 6蛋白可以抑制蛋白酶体抑制剂，有没有证据ER应力或激活的未折叠的蛋白质反应，在出生后的发展过程中，在不同的大脑区域。观察到LC 3-II、泛素化蛋白和神经元p62阳性聚集体的α-依赖性增加，表明nclf小鼠脑中蛋白质的自噬-溶酶体降解途径的破坏，最可能是由于自噬体和溶酶体之间的融合缺陷。这些数据表明，蛋白酶体降解的突变Cln 6是足以防止积累的错误折叠的Cln 6蛋白，而溶酶体功能障碍损害组成性自噬促进神经变性。
Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age-dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration.
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DOI：
10.1016/j.bbadis.2006.08.002
发表时间：
2006-10-01
影响因子：
6.2
作者：
Cooper, Jonathan D.;Russell, Claire;Mitchison, Hannah M.
通讯作者：
Mitchison, Hannah M.
影响因子：
9.8
作者：
Gao, HL;Boustany, RMN;MacDonald, ME
通讯作者：
MacDonald, ME
影响因子：
4.7
作者：
Jabs, Sabrina;Quitsch, Arne;Braulke, Thomas
通讯作者：
Braulke, Thomas
影响因子：
3.9
作者：
Kurze, Anna-Katherina;Galliciotti, Giovanna;Braulke, Thomas
通讯作者：
Braulke, Thomas
影响因子：
6.4
作者：
Kay, Graham W.;Palmer, David N.;Cooper, Jonathan D.
通讯作者：
Cooper, Jonathan D.