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BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain-Implications for Neurodegeneration.
Antioxidants ( IF 6.0 ) Pub Date : 2020-07-27 , DOI: 10.3390/antiox9080671
Chiara Lanzillotta 1 , Ilaria Zuliani 1 , Chirag Vasavda 2 , Solomon H Snyder 2, 3, 4 , Bindu D Paul 2 , Marzia Perluigi 1 , Fabio Di Di Domenico 1 , Eugenio Barone 1
Affiliation  

Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A/) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3, LC3II/I ratio, Atg5–Atg12 complex and Atg7 in the cortex of BVR-A/ mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy.

中文翻译:

BVR-A 缺陷通过 AMPK/mTOR 轴的失调导致自噬受损 - 神经退行性疾病的大脑影响。

胆绿素还原酶-A (BVR-A) 损伤与氧化损伤蛋白质的积累增加以及神经退行性疾病期间大脑中自噬的损伤有关。减少的自噬抑制错误折叠蛋白的清除,然后形成促进神经元死亡的神经毒性聚集体。我们研究的目的是通过评估从 BVR-A 敲除中收集的大脑皮层样本的年龄相关变化(2、6 和 11 个月),阐明 BVR-A 在调节 mTOR/自噬轴中的作用。 BVR-A - / -) 和野生型 (WT) 小鼠。我们的结果表明,BVR-A 缺乏导致氧化损伤蛋白质的积累以及皮层中 mTOR 的过度激活。这个过程始于幼鼠,并随着衰老而持续。mTOR 过度激活与自噬受损有关,BVR-A - / -小鼠皮层中 Beclin-1、LC3、LC3II/I 比率、Atg5-Atg12 复合物和 Atg7 的水平降低突出了这一点。此外,我们已经确定 AMP 活化蛋白激酶 (AMPK) 的失调是在没有 BVR-A 的情况下驱动 mTOR 过度激活的关键事件。总体而言,我们的研究结果表明 BVR-A 是自噬调节的新参与者,其可能旨在为涉及自噬受损的疾病提供新的治疗方法。
更新日期:2020-07-27
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