Transcription Factor EB Is Selectively Reduced in the Nuclear Fractions of Alzheimer's and Amyotrophic Lateral Sclerosis Brains.
Transcription Factor EB Is Selectively Reduced in the Nuclear Fractions of Alzheimer's and Amyotrophic Lateral Sclerosis Brains.
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DOI：
10.1155/2016/4732837
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Lakshmana MK
中科院分区：
文献类型：
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作者：
Wang H;Wang R;Xu S;Lakshmana MK
多项研究表明，自噬在阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）中严重失调，如患者大脑中大量自噬体、具有不连续膜的溶酶体和聚集蛋白质的积累所证明。转录因子EB（TFEB）是近年来发现的一种主要的溶酶体生物合成和自噬调节因子。为了检查AD和ALS中的异常自噬是否是由于TFEB表达的改变，我们通过免疫印迹系统地定量了这些大脑中TFEB的水平。有趣的是，AD脑的细胞质部分仅在Braak IV期显示出标准化（相对于微管蛋白）TFEB水平的增加（61%，p < 0.01）。最重要的是，当与正常对照（NC）脑相比时，从Braak IV期（52%，p < 0.01）、V期（67%，p < 0.01）和VI期（85%，p < 0.01）开始，核级分中的标准化（相对于核纤层蛋白）TFEB水平持续降低。在ALS脑中，核TFEB水平也降低了62%（p < 0.001）。这些数据表明，在ALS以及AD脑中，选择性地丢失核TFEB，其中TFEB减少是Braak阶段依赖性的。总之，观察到的TFEB蛋白水平的降低可能是这些疾病中广泛报道的自噬缺陷的原因。
Multiple studies suggest that autophagy is strongly dysregulated in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), as evidenced by accumulation of numerous autophagosomes, lysosomes with discontinuous membranes, and aggregated proteins in the patients' brains. Transcription factor EB (TFEB) was recently discovered to be a master regulator of lysosome biogenesis and autophagy. To examine whether aberrant autophagy in AD and ALS is due to alterations in TFEB expression, we systematically quantified the levels of TFEB in these brains by immunoblotting. Interestingly, cytoplasmic fractions of AD brains showed increased levels of normalized (to tubulin) TFEB only at Braak stage IV (61%, p < 0.01). Most importantly, normalized (to lamin) TFEB levels in the nuclear fractions were consistently reduced starting from Braak stage IV (52%, p < 0.01), stage V (67%, p < 0.01), and stage VI (85%, p < 0.01) when compared to normal control (NC) brains. In the ALS brains also, nuclear TFEB levels were reduced by 62% (p < 0.001). These data suggest that nuclear TFEB is selectively lost in ALS as well as AD brains, in which TFEB reduction was Braak-stage-dependent. Taken together, the observed reductions in TFEB protein levels may be responsible for the widely reported autophagy defects in these disorders.