Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.
Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.
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DOI：
10.1093/hmg/ddw429
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发表时间：
2017-02-15
影响因子：
3.5
通讯作者：
Kiaei M
中科院分区：
文献类型：
--
作者：
Fil D;DeLoach A;Yadav S;Alkam D;MacNicol M;Singh A;Compadre CM;Goellner JJ;O'Brien CA;Fahmi T;Basnakian AG;Calingasan NY;Klessner JL;Beal FM;Peters OM;Metterville J;Brown RH Jr;Ling KKY;Rigo F;Ozdinler PH;Kiaei M
最近在25个家族性ALS病例中鉴定出profilin 1突变，将这种细胞因子调节蛋白的功能改变与运动神经元疾病的发病机制联系起来。为了研究突变profilin 1在运动神经元疾病中的病理作用，我们产生了表达人profilin 1的转基因小鼠系，其在位置118处具有突变（hPFN 1 G118 V）。在脑和脊髓中表达高水平突变型人PFN 1蛋白的小鼠品系之一表现出与人ALS疾病一致的许多关键临床和病理学特征。这些包括下（腹角）和上运动神经元（第V层中的皮质脊髓运动神经元）的丢失、突变的profilin 1聚集、异常泛素化蛋白、胆碱乙酰转移酶（ChAT）表达减少、线粒体片段化、神经胶质细胞活化、肌肉萎缩、体重减轻和存活率降低。我们的肌动蛋白动力学和轴突完整性的调查表明，突变PFN 1蛋白与异常低的丝状/球状（F/G）-肌动蛋白的比例，可能是导致沃勒样变性的腹根轴突严重损伤的根本原因。这些观察结果表明，我们的新型profilin 1突变小鼠系可能提供了一种新的ALS模型，有机会获得独特的观点，神经退行性变的机制，有助于ALS的发病机制。
The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function of this cytoskeleton-regulating protein to the pathogenesis of motor neuron disease. To investigate the pathological role of mutant profilin1 in motor neuron disease, we generated transgenic lines of mice expressing human profilin1 with a mutation at position 118 (hPFN1 G118V ). One of the mouse lines expressing high levels of mutant human PFN1 protein in the brain and spinal cord exhibited many key clinical and pathological features consistent with human ALS disease. These include loss of lower (ventral horn) and upper motor neurons (corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, glial cell activation, muscle atrophy, weight loss, and reduced survival. Our investigations of actin dynamics and axonal integrity suggest that mutant PFN1 protein is associated with an abnormally low filamentous/globular (F/G)-actin ratio that may be the underlying cause of severe damage to ventral root axons resulting in a Wallerian-like degeneration. These observations indicate that our novel profilin1 mutant mouse line may provide a new ALS model with the opportunity to gain unique perspectives into mechanisms of neurodegeneration that contribute to ALS pathogenesis.
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DOI：
10.1093/cercor/bhu318
发表时间：
2015-11
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Jara JH;Genç B;Cox GA;Bohn MC;Roos RP;Macklis JD;Ulupınar E;Özdinler PH
通讯作者：
Özdinler PH
影响因子：
4.2
作者：
Abramzon Y;Johnson JO;Scholz SW;Taylor JP;Brunetti M;Calvo A;Mandrioli J;Benatar M;Mora G;Restagno G;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
4.2
作者：
Ingre, Caroline;Landers, John E.;Weishaupt, Jochen H.
通讯作者：
Weishaupt, Jochen H.
影响因子：
4.5
作者：
Huang C;Zhou H;Tong J;Chen H;Liu YJ;Wang D;Wei X;Xia XG
通讯作者：
Xia XG
影响因子：
3.5
作者：
Gautam M;Jara JH;Sekerkova G;Yasvoina MV;Martina M;Özdinler PH
通讯作者：
Özdinler PH