Failure to Thrive: Impaired BDNF Transport along the Cortical-Striatal Axis in Mouse Q140 Neurons of Huntington's Disease.
Failure to Thrive: Impaired BDNF Transport along the Cortical-Striatal Axis in Mouse Q140 Neurons of Huntington's Disease.
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DOI：
10.3390/biology12020157
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发表时间：
2023-01-19
期刊：
影响因子：
4.2
通讯作者：
Yang, Yanmin
中科院分区：
文献类型：
--
作者：
Maloney, Michael T.;Wang, Wei;Bhowmick, Sumana;Millan, Ivan;Kapur, Mridu;Herrera, Nicolas;Frost, Everett;Zhang, Elena Y.;Song, Scott;Wang, Melissa;Park, Amelia Bora;Yao, Annabelle Y.;Yang, Yanmin
关键词：
脑源性神经营养因子（BDNF）与纹状体神经元的功能和存活有关。BDNF的神经营养支持缺陷被认为是亨廷顿病（HD）纹状体神经元神经退行性变的原因。本文概述了从HD小鼠Q140模型分离的原代神经元中BDNF沿皮质纹状体轴运输缺陷的研究。在这里，我们采用了一种微流体室细胞培养系统，专门用于培养皮质纹状体共培养。在这个系统中，我们使用量子点共轭BDNF （QD-BDNF）来可视化BDNF在轴突和树突运输过程中的单分子运输行为。我们发现QD-BDNF的供应在沿皮质轴突顺行和Q140初级神经元纹状体树突逆行中存在全球性缺陷。这些发现支持了BDNF对纹状体神经元的基本时空支持由于其皮层-纹状体运输缺陷而减少的观点，这一缺陷导致了HD的纹状体神经变性。BDNF营养支持已被提出作为一种治疗干预措施，以延缓或预防神经退行性疾病的发生和进展。我们的研究为涉及BDNF补充的治疗策略如何应用于亨廷顿舞蹈症或其他疾病提供了额外的见解。通过增加脑源性神经营养因子（BDNF）水平来增强纹状体神经元的营养支持被认为是几种神经退行性疾病（包括亨廷顿病（HD））治疗干预的靶点。为了帮助实施这一战略，对脑源性神经细胞皮层-纹状体转运的全面了解对于指导其战略实施至关重要。在这篇论文中，我们研究了BDNF在HD小鼠模型Q140初级神经元中沿皮质纹状体轴运输的动态行为。我们通过使用量子点共轭BDNF （QD-BDNF）的单分子标记，在专门设计用于皮质和纹状体初级神经元共培养的微流控室系统中，跟踪沿皮质-纹状体轴的运输来检验这一点。通过这种方法，我们观察到了Q140神经元中QD-BDNF转运的缺陷。我们的研究表明，QD-BDNF沿皮质纹状体轴的运输涉及皮层神经元轴突内的顺行运输和纹状体神经元树突内的逆行运输的损害。我们观察到的一个显著特征是Q140纹状体树突内QD-BDNF逆行转运的暂停时间延长。综上所述，这些发现支持了一种假设，即在运输受损的驱动下，BDNF对纹状体神经元的不良时空营养支持可能有助于HD的发病机制，这为我们提供了如何将BDNF补充治疗策略最佳地应用于HD的见解。
The brain-derived neurotrophic factor (BDNF) is implicated in the function and survival of striatal neurons. Deficits in neurotrophic support by BDNF have been hypothesized to contribute to the neurodegeneration of striatal neurons in Huntington’s disease (HD). This article outlines an investigation into defects in the transport of BDNF along the cortical–striatal axis in primary neurons isolated from the Q140 mouse model of HD. Herein we employ a microfluidic chamber cell culture system specifically designed to grow cortical–striatal co-cultures. Within this system, we employed quantum dot-conjugated BDNF (QD-BDNF) to visualize single-molecule transport behaviors of BDNF undergoing axonal and dendritic transport. We found a global defect in the supply of QD-BDNF moving anterogradely along cortical axons, and retrogradely within the striatal dendrites of Q140 primary neurons. These findings support the notion that the essential spatiotemporal support from BDNF to striatal neurons is reduced due to deficits in its cortical–striatal transport, a defect contributing to striatal neurodegeneration in HD. BDNF trophic support has been proposed as a therapeutic intervention to delay or prevent the onset and progression of neurodegenerative diseases. Our study provides additional insight into how therapeutic strategies involving BDNF supplementation may be applied for Huntington’s or other diseases. Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington’s disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical–striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical–striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical–striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical–striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.
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