美国哈佛医学院Rudolph E. Tanzi、Huda Y. Zoghbi以及Jaehong Suh研究组的合作发现ATXN-1的缺失提高脑BACE1的转录水平，并增强老年痴呆症的发病。该研究于2019年8月22日发表于国际学术期刊《细胞》。
ATXN1与阿尔茨海默病（AD）风险增加有关，但AD患者的CAG重复数目并没有改变。课题组研究了ataxin-1功能丧失的后果，并发现Atxn1的敲除减少了CIC-ETV4/5介导的Bace1转录抑制，导致BACE1水平升高和APP的淀粉样蛋白（选择性地聚集在AD易感脑区域）断裂增多。升高的BACE1表达加剧了AD小鼠模型中的Aβ沉积和神经胶质增生，并且损害了海马体神经发生和嗅觉轴突靶向。在脊髓小脑性共济失调1型症（SCA1）小鼠中，多聚谷氨酰胺扩增的突变体ataxin-1导致BACE1在大脑和小脑中转录后修饰增加，并且在海马CA2区域中引起轴突靶向缺陷和神经退行性病变。这些结果表明，ataxin-1的缺失会促进BACE1的表达和Aβ病变，使其成为可能的AD诱因和致病原因。
据了解，ATXN1中CAG三核苷酸重复序列的扩增导致SCA1，这是一种损害协调和认知的神经退行性疾病。
附：英文原文
Title: Loss of Ataxin-1 Potentiates Alzheimer’s Pathogenesis by Elevating Cerebral BACE1 Transcription
Author: Jaehong Suh,Donna M. Romano,Larissa Nitschke,Scott P. Herrick,Britt A. DiMarzio,Volodymyr Dzhala,Jun-Seok Bae,Mary K. Oram,Yuejiao Zheng,Basavaraj Hooli,Kristina Mullin,Vincenzo A. Gennarino 8,Wilma Wasco,Jeremy D. Schmahmann,Mark W. Albers,Huda Y. Zoghbi,Rudolph E. Tanzi
Issue&Volume:Volume 178 Issue 5
Abstract: Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer’s disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aβ deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aβ pathology, rendering it a potential contributor to AD risk and pathogenesis.
DOI: https://doi.org/10.1016/j.cell.2019.07.043
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30843-8