当前位置: X-MOL 学术Brain › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin
Brain ( IF 10.6 ) Pub Date : 2018-03-09 , DOI: 10.1093/brain/awy057
Laurie Galvan 1, 2 , Laetitia Francelle 1, 2 , Marie-Claude Gaillard 1, 2 , Lucie de Longprez 1, 2 , Maria-Angeles Carrillo-de Sauvage 1, 2 , Géraldine Liot 1, 2, 3, 4, 5 , Karine Cambon 1, 2 , Lev Stimmer 1, 6 , Sophie Luccantoni 1, 6 , Julien Flament 1, 6 , Julien Valette 1, 2 , Michel de Chaldée 7 , Gwenaelle Auregan 1, 2 , Martine Guillermier 1, 2 , Charlène Joséphine 1, 2 , Fanny Petit 1, 2 , Caroline Jan 1, 2 , Margot Jarrige 8, 9 , Noëlle Dufour 1, 2 , Gilles Bonvento 1, 2 , Sandrine Humbert 3, 4, 5 , Frédéric Saudou 3, 4, 5 , Philippe Hantraye 1, 2 , Karine Merienne 10 , Alexis-Pierre Bemelmans 1, 2 , Anselme L Perrier 8, 9 , Nicole Déglon 11, 12 , Emmanuel Brouillet 1, 2
Affiliation  

The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington’s disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington’s disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington’s disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration.

中文翻译:

纹状体激酶DCLK3对突变亨廷顿蛋白产生神经保护作用

大脑中表达的多种激酶的神经生物学功能尚不清楚。在这里,我们报告有关DCLK3(双皮质激素样激酶3)的新发现,该物质优先在纹状体和齿状回的神经元中表达。其功能从未被研究过。在亨廷顿氏病中,DCLK3表达显着降低。在与癌症有关的研究中获得的最新数据表明,DCLK3可能具有抗凋亡作用。因此,我们假设亨廷顿氏病中DCLK3的早期缺失可能使纹状体神经元更易受到突变亨廷顿蛋白(mHtt)的影响。我们发现小鼠纹状体中的DCLK3沉默加剧了mHtt的N端片段的毒性。相反,DCLK3的过表达减少了mHtt产生的神经变性。在亨廷顿舞蹈症的敲入小鼠模型中,DCLK3还对运动症状产生了有益的影响。使用DCLK3的不同突变体,我们发现该蛋白的激酶活性在神经保护中起关键作用。为了研究DCLK3效应的潜在机制,我们研究了文化中人纹状体神经元中激酶结构域产生的转录变化。结果表明,DCLK3以激酶依赖性方式调节许多参与转录调节和核小体/染色质重塑的基因的表达。与此相符的是,组织学评估表明,纹状体神经元的核中存在DCLK3,蛋白质-蛋白质相互作用实验表明,激酶结构域与锌指蛋白质(包括转录激活接头TADA3)相互作用,Spt-ada-Gcn5乙酰基转移酶(SAGA)复合物的核心成分,可将组蛋白乙酰化与转录机制联系起来。我们的新发现表明,纹状体神经元中DCLK3的存在可能在这些脑细胞的转录调节和染色质重塑中起关键作用,并表明在亨廷顿舞蹈病中该激酶的表达降低可能使纹状体高度易受神经变性的影响。
更新日期:2018-03-09
down
wechat
bug