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Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

机译:在创伤性脑损伤后,自噬助剂有受损的自噬助体与神经细胞死亡有关

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Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1-3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death.
机译:自噬的失调促成了几种神经变性和溶酶体储存疾病中的神经元细胞死亡。创伤性脑损伤(TBI)后,自噬标记也增加,但其机制和功能尚不清楚。在GFP-LC3(绿色荧光蛋白-LC3)转基因小鼠中受控皮质冲击(CCI)脑损伤,我们观察到在1至7天的同侧皮质和海马中的自噬物的积累。由于通过自噬底物Sqstm1 / p62(封装1)的积累反射,因此该累积不会增加自噬的开始,而是减少自噬囊体的间隙。这是通过离体研究证实的,与对照动物相比,脑切片中展示了脑切片中的缓冲助剂。增加SQSTM1在D 1-3处达到达到达到的,但是D 7分辨,表明自噬助焊剂中的缺陷是暂时的。自噬的早期损害至少部分是由溶酶体功能障碍引起的,如较低的蛋白质水平和CTSD(组织蛋白酶D)的酶活性所证明的。此外,在损伤后立即在神经元中累积的自噬骨骺和SQSTM1。这伴随着受影响的细胞中Sqstm1和泛素阳性斑点的外观,表明,类似于神经变性疾病中观察到的情况,自噬受损可能有助于神经元损伤。始终如一地,GFP-LC3和SQSTM1与近端损伤部位近端的神经元细胞中依赖于胱天蛋白酶依赖性和依赖性细胞死亡的标志物。连同,我们的数据首次表明,由于溶酶体功能障碍,TBI早期自噬清除损害,并与神经元细胞死亡相关。

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