GATA1-mediated transcriptional regulation of the γ-secretase activating protein increases Aβ formation in Down syndrome.
GATA1-mediated transcriptional regulation of the γ-secretase activating protein increases Aβ formation in Down syndrome.
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DOI：
10.1002/ana.24540
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发表时间：
2016-01
影响因子：
11.2
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Chu J;Wisniewski T;Praticò D
由于21号染色体上Aβ前体蛋白基因的额外拷贝，唐氏综合症(DS)患者在生命早期就会出现高水平的Aβ多肽和阿尔茨海默病样脑淀粉样变性。在这里，我们发现γ-分泌酶激活蛋白(GSAP)是淀粉样变发生的关键酶，在DS脑中增加，并在转录水平上受到GATA1转录因子的特异性调节。这一新途径的发现对DS具有翻译意义，因为药物抑制GSAP是一种有吸引力且可行的降低Aβ的治疗策略。
Because of an extra copy of the Aβ precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Aβ peptides and Alzheimer disease–like brain amyloidosis early in life. Here we show that the γ-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Aβ-lowering therapeutic strategy for this disorder.