Lithium rescues the impaired autophagy process in CbCln3(Δex7/8/Δex7/8) cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition.
Lithium rescues the impaired autophagy process in CbCln3(Δex7/8/Δex7/8) cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition.
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DOI：
10.1111/j.1471-4159.2010.07158.x
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发表时间：
2011-02
影响因子：
4.7
通讯作者：
Jung YK
中科院分区：
文献类型：
--
作者：
Chang JW;Choi H;Cotman SL;Jung YK
幼年神经元样脂褐质病（JNCL或Batten病）是一种由CLN3突变引起的神经退行性疾病。先前在Cln3突变敲入小鼠中发现了缺陷的自噬和伴随的富含线粒体ATP合成酶亚基c的自身荧光的积累。在这里，我们表明锂处理减少了lc3阳性自噬体的数量和LC3-II在Cln3突变敲入的小脑细胞中的积累（CbCln3Δex7/8/Δex7/8）。锂作为GSK3和IMPase的抑制剂，可减少CbCln3Δex7/8/Δex7/8细胞中线粒体ATP合酶亚基c和自身荧光的积累，减轻细胞中酸性囊泡的异常亚细胞分布。l690330是一种IMPase抑制剂，在CbCln3Δex7/8/Δex7/8细胞中与锂一样有效地恢复自噬。此外，锂离子或下调IMPase表达可保护CbCln3Δex7/8/Δex7/8细胞免受氨基酸剥夺引起的细胞死亡。这些结果表明，锂可能通过IMPase克服了CbCln3Δex7/8/Δex7/8小脑细胞的自噬缺陷，从而降低了它们对细胞死亡的易感性。
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) is a neurodegenerative disorder caused by mutation in CLN3. Defective autophagy and concomitant accumulation of autofluorescence enriched with mitochondrial ATP synthase subunit c were previously discovered in Cln3 mutant knock-in mice. Here we show that treatment with lithium reduces numbers of LC3-positive autophagosomes and accumulation of LC3-II in Cln3 mutant knock-in cerebellar cells (CbCln3Δex7/8/Δex7/8). Lithium, an inhibitor of GSK3 and IMPase, reduces the accumulation of mitochondrial ATP synthase subunit c and autofluorescence in CbCln3Δex7/8/Δex7/8 cells, and mitigates the abnormal subcellular distribution of acidic vesicles in the cells. L690,330, an IMPase inhibitor, is as effective as lithium in restoring autophagy in CbCln3Δex7/8/Δex7/8 cells. Moreover, lithium or downregulation of IMPase expression protects CbCln3Δex7/8/Δex7/8 cells from cell death induced by amino acid deprivation. These results suggest that lithium overcomes the autophagic defect in CbCln3Δex7/8/Δex7/8 cerebellar cells probably through IMPase, thereby reducing their vulnerability to cell death.