Zhao Xiaobei, Chen Xu-Qiao, Han Eugene, Hu Yue, Paik Paul, Ding Zhiyong, Overman Julia, Lau Alice L, Shahmoradian Sarah H, Chiu Wah, Thompson Leslie M, Wu Chengbiao, Mobley William C
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
The University of Texas M. D. Anderson Cancer Center, Houston, TX 77054;
Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):E5655-64. doi: 10.1073/pnas.1603020113. Epub 2016 Sep 6.
Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.
皮质纹状体萎缩是亨廷顿舞蹈症（HD）的主要表现。然而，突变型亨廷顿蛋白（mHTT）导致皮质纹状体回路退化的机制尚不清楚。我们在微流控腔室中重建了皮质纹状体回路，将HD的BACHD模型及其野生型对照的皮质神经元和纹状体神经元配对。在将BACHD皮质神经元和纹状体神经元配对的培养物中，突触连接减少，纹状体神经元萎缩。然而，如果将野生型皮质神经元与BACHD纹状体神经元配对，这些变化就会得到预防；这是由野生型皮质轴突合成和释放脑源性神经营养因子（BDNF）所致。与这些发现一致，BACHD皮质神经元中BDNF的顺行运输显著减少。胞质伴侣蛋白T复合体1（TCP-1）环复合体（TRiC或含TCP-1的伴侣蛋白CCT）的亚基已被证明可降低mHTT水平。CCT3和CCT1的顶端结构域（ApiCCT1）均降低了BACHD皮质神经元中mHTT的水平。在皮质轴突中，它们使BDNF的顺行运输正常化，恢复BDNF的逆行运输，并使溶酶体运输正常化。重要的是，用ApiCCT1处理BACHD皮质神经元可通过增强BDNF的释放来预防BACHD纹状体神经元萎缩，BDNF随后通过纹状体神经元上的酪氨酸受体激酶B（TrkB）受体发挥作用。我们的研究结果证明，TRiC试剂介导的mHTT减少增强了BDNF的传递，从而恢复了BACHD纹状体神经元的营养状态。
