A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction.
A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction.
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DOI：
10.1093/brain/awx005
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发表时间：
2017-04-01
期刊：
影响因子：
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通讯作者：
Rubinsztein DC
中科院分区：
文献类型：
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作者：
Lopez A;Lee SE;Wojta K;Ramos EM;Klein E;Chen J;Boxer AL;Gorno-Tempini ML;Geschwind DH;Schlotawa L;Ogryzko NV;Bigio EH;Rogalski E;Weintraub S;Mesulam MM;Tauopathy Genetics Consortium;Fleming A;Coppola G;Miller BL;Rubinsztein DC
MAPT的突变引起多种神经退行性疾病。Lopez等人证实，a152t变异tau与额颞叶痴呆和进行性核上麻痹综合征的风险增加有关。在表达A152T-tau的斑马鱼中，自噬的上调增加了tau清除并改善了病理，这表明了治疗tau病变的潜力。编码tau （MAPT）基因的突变导致额颞叶痴呆谱系障碍。在一项初步的病例对照研究中，一种罕见的tau变体p.A152T被报道为额颞叶痴呆谱和阿尔茨海默病的危险因素。这些发现需要在一个独立的队列中进行复制。我们分析了一个独立的多国队列，包括3100名神经退行性疾病患者和4351名健康对照者，发现p.A152T与临床定义的额颞叶痴呆和进行性核上麻痹综合征的风险显著升高相关。为了评估这种变异的功能和生化后果，我们建立了表达野生型或A152T-tau的转基因斑马鱼模型，其中A152T导致神经变性和蛋白酶体受损。蛋白酶体活性受损也可能增加与该变异相关的其他蛋白质的积累。我们通过自噬的药理学和遗传上调来提高A152T清除动力学，并改善在A152T-tau鱼中观察到的疾病病理。因此，自噬上调疗法可能是治疗牛头病变的一种策略。
Mutations in MAPT cause a variety of neurodegenerative disorders. Lopez et al. confirm that A152T-variant tau is associated with increased risk for frontotemporal dementia and progressive supranuclear palsy syndrome. Upregulation of autophagy increases tau clearance and ameliorates pathology in zebrafish expressing A152T-tau, suggesting potential for the treatment of tauopathies. Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer’s disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.