Staufen1 in Human Neurodegeneration.
Staufen1 in Human Neurodegeneration.
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Staufen1在人类神经变性中的作用
DOI：
10.1002/ana.26069
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发表时间：
2021-06
影响因子：
11.2
通讯作者：
Pulst SM
中科院分区：
文献类型：
--
作者：
Paul S;Dansithong W;Figueroa KP;Gandelman M;Scoles DR;Pulst SM
ATXN2基因突变（CAG扩增≥32次重复）可能是帕金森病和肌萎缩侧索硬化症（ALS）的罕见病因。我们最近报道了应激颗粒（SG）蛋白Staufen1 （STAU1）在神经退行性疾病脊髓小脑性共济失调2型（SCA2）患者细胞、动物模型和ALS-TDP-43成纤维细胞中过量表达，并提供了SG形成和自噬之间的联系。我们的目的是测试STAU1的过度表达是否在其他神经退行性疾病的发病机制中起作用。通过多种神经退行性患者来源的细胞模型、动物模型和人死后ALS组织，我们使用生化和免疫组织学分析来评估STAU1的功能。我们在TDP-43突变的ALS患者、PSEN1突变的痴呆患者、MAPT突变的帕金森患者、亨廷顿氏病（HD）突变的患者和SCA2突变的患者的成纤维细胞中发现了STAU1过丰和增加的总和磷酸化的哺乳动物雷帕霉素靶点（mTOR）。在人类ALS脊髓组织和动物模型中，可以看到STAU1水平和mTOR活性的增加。STAU1和mTOR蛋白水平的变化发生在转录后。在野生型细胞中外源表达STAU1足以激活mTOR和下游靶点，形成SGs。通过RNAi正常化mTOR靶向STAU1，提示在与STAU1过量相关的疾病的治疗中具有潜在作用。神经退行性疾病中STAU1的过度表达是与mTOR过度活跃相关的常见现象。用ASOs或miRNA病毒载体靶向STAU1可能是一种新的、有效的治疗以STAU1过丰富为特征的神经退行性疾病的方法。
Mutations in the ATXN2 gene (CAG expansions ≥32 repeats) can be a rare cause of Parkinson’s disease and amyotrophic lateral sclerosis (ALS). We recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy. We aimed to test if STAU1 overabundance has a role in the pathogenesis of other neurodegenerative diseases. With multiple neurodegenerative patient-derived cell models, animal models, and human postmortem ALS tissue, we evaluate STAU1 function using biochemical and immunohistological analyses. We demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington’s disease (HD) mutations, and SCA2 mutations. Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs. Targeting STAU1 by RNAi normalized mTOR, suggesting a potential role for therapy in diseases associated with STAU1 overabundance. STAU1 overabundance in neurodegeneration is a common phenomenon associated with hyperactive mTOR. Targeting STAU1 with ASOs or miRNA viral vectors may represent a novel, efficacious therapy for neurodegenerative diseases characterized by overabundant STAU1.
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肌萎缩性侧索硬化和额颞痴呆的TIA1突变促进相位分离并改变应激颗粒动力学。
影响因子：
16.2
作者：
Mackenzie IR;Nicholson AM;Sarkar M;Messing J;Purice MD;Pottier C;Annu K;Baker M;Perkerson RB;Kurti A;Matchett BJ;Mittag T;Temirov J;Hsiung GR;Krieger C;Murray ME;Kato M;Fryer JD;Petrucelli L;Zinman L;Weintraub S;Mesulam M;Keith J;Zivkovic SA;Hirsch-Reinshagen V;Roos RP;Züchner S;Graff-Radford NR;Petersen RC;Caselli RJ;Wszolek ZK;Finger E;Lippa C;Lacomis D;Stewart H;Dickson DW;Kim HJ;Rogaeva E;Bigio E;Boylan KB;Taylor JP;Rademakers R
通讯作者：
Rademakers R
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
4
作者：
Gabriela Thomas, Maria;Martinez Tosar, Leandro J.;Boccaccio, Graciela L.
通讯作者：
Boccaccio, Graciela L.
影响因子：
16.2
作者：
Barbee, Scott A.;Estes, Patricia S.;Ramaswami, Mani
通讯作者：
Ramaswami, Mani