Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease.
Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease.
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突触核蛋白损害帕金森病小鼠模型中 BDNF 的运输和信号传导
DOI：
10.1038/s41598-017-04232-4
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发表时间：
2017-06-20
影响因子：
4.6
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Fang F;Yang W;Florio JB;Rockenstein E;Spencer B;Orain XM;Dong SX;Li H;Chen X;Sung K;Rissman RA;Masliah E;Ding J;Wu C
最近的研究表明，tau 蛋白的过度磷酸化在神经退行性疾病中的 α-突触核蛋白 (ASYN) 神经元毒性中发挥作用，例如家族性阿尔茨海默病 (AD)、路易体痴呆 (DLB) 和帕金森病。使用表达由 PDGF-β 启动子驱动的 GFP-ASYN 的帕金森病 (PD) 转基因小鼠模型，我们研究了 ASYN 的积累如何影响轴突功能。我们发现，在 E18 皮质神经元的 DIV7 培养物中，脑源性神经营养因子 (BDNF) 的逆行轴突运输在胚胎阶段明显受损，尽管在此阶段在这些神经元中未检测到 tau 的过度磷酸化。有趣的是，我们发现过表达的 ASYN 与动力蛋白相互作用，并诱导小 Rab GTP 酶（如 Rab5 和 Rab7）的激活水平显着增加，这两种酶都是内吞过程的关键调节因子。此外，ASYN 的表达导致 E18 转基因小鼠模型或用 ASYN-GFP 瞬时转染 72 小时的大鼠 E18 胚胎的 DIV7 皮层培养物中的神经元萎缩。我们的研究表明，过量的 ASYN 可能会改变内吞途径，导致 PD 小鼠模型中胚胎皮质神经元的轴突功能障碍。
Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of α-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease. Using a transgenic mouse model of Parkinson’s disease (PD) that expresses GFP-ASYN driven by the PDGF-β promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models.