Erratum: Overexpression of BDNF and Full-Length TrkB Receptor Ameliorate Striatal Neural Survival in Huntington's Disease

<b><i>Background:</i></b> Several cellular mechanisms have been proposed to explain the pathogenesis of Huntington's disease (HD), including the lack of striatal brain-derived neurotrophic factor (BDNF). Thus, by preferentially binding to tropomyosin receptor kinase B (TrkB) receptor, BDNF is an important neurotrophin implicated in striatal neuronal survival. <b><i>Objective:</i></b> To study the influence of BDNF and TrkB receptors in intracellular signaling pathways and caspase-3 activation in HD striatal cells. <b><i>Methods:</i></b> HD mutant knockin and wild-type striatal cells were transduced with preproBDNF or full-length TrkB receptors to analyze BDNF processing, AKT and extracellular signal-regulated kinase (ERK) activation and the activity of caspase-3 in the absence or presence of staurosporine (STS). <b><i>Results:</i></b> HD mutant cells transduced with preproBDNF-mCherry (mCh) expressed similar levels of pro- and mature BDNF compared to WT cells, but HD cells released lower levels of pro- and mature BDNF. Despite this, BDNF-mCh overexpression rescued decreased AKT phosphorylation and reduced the caspase-3 activation observed in HD cells. Activated ERK was also enhanced in HD BDNF-mCh/TrkB-eGFP receptor co-cultures. Of relevance, overexpression of TrkB-eGFP in HD cells decreased caspase-3 activation, and stimulation of TrkB-eGFP-transduced mutant cells with recombinant human BDNF reduced both basal and STS-induced caspase-3 activation. <b><i>Conclusion:</i></b> The results highlight the importance of BDNF-induced TrkB receptor signaling in rescuing HD-mediated apoptotic features in striatal cells.

<b><i>背景:</i></b> 目前已有多种细胞机制被提出，用以阐释亨廷顿舞蹈症（Huntington's disease, HD）的发病机制，其中包括纹状体脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）的缺失。BDNF可通过优先结合原肌球蛋白受体激酶B（tropomyosin receptor kinase B, TrkB）受体，是参与纹状体神经元存活的关键神经营养因子。<b><i>目的:</i></b> 探究BDNF与TrkB受体对亨廷顿舞蹈症纹状体细胞内信号通路及半胱天冬酶-3（caspase-3）激活的影响。<b><i>方法:</i></b> 将亨廷顿舞蹈症突变敲入细胞与野生型纹状体细胞，分别转导preproBDNF或全长TrkB受体，以在存在或不存在星形孢菌素（staurosporine, STS）的条件下，分析BDNF的加工过程、AKT及细胞外信号调节激酶（extracellular signal-regulated kinase, ERK）的激活情况，以及半胱天冬酶-3的活性。<b><i>结果:</i></b> 转导preproBDNF-红色荧光蛋白(mCherry, mCh)的HD突变细胞，其前体BDNF（pro-BDNF）与成熟BDNF的表达水平与野生型（WT）细胞相近，但HD突变细胞释放的前体及成熟BDNF水平更低。尽管存在这一差异，过表达BDNF-mCh可挽救HD细胞中AKT磷酸化水平降低的表型，并抑制检测到的半胱天冬酶-3激活。在共转导BDNF-mCh与TrkB-增强型绿色荧光蛋白(eGFP)的细胞培养体系中，激活的ERK水平亦得到显著提升。值得关注的是，在HD细胞中过表达TrkB-eGFP可降低半胱天冬酶-3的激活；而用重组人BDNF刺激转导了TrkB-eGFP的突变细胞，可同时降低基础水平及星形孢菌素诱导的半胱天冬酶-3激活。<b><i>结论:</i></b> 本研究结果凸显了BDNF介导的TrkB受体信号通路在挽救HD诱导的纹状体细胞凋亡特征中的重要作用。