Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.
Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.
复制标题
DOI：
10.3389/fnagi.2023.1223911
复制
发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
亨廷顿病（HD）是一种以运动和认知功能障碍为特征的神经退行性疾病。HD是由亨廷顿基因（HTT）外显子1中的CAG重复序列扩增引起的，这导致亨廷顿蛋白中出现多聚谷氨酰胺（PQ）重复序列，该蛋白在大脑和外周聚集。此前，我们利用果蝇模型确定了心脏中的亨廷顿蛋白 - PQ聚集会导致寿命缩短和心脏功能障碍，而促进伴侣蛋白功能或减少氧化应激可改善这种情况。在此，我们进一步研究了神经元突变型亨廷顿蛋白的作用以及它如何影响外周功能。我们在果蝇神经元中过表达正常的（亨廷顿蛋白 - PQ25）或扩增的突变型（亨廷顿蛋白 - PQ72）亨廷顿蛋白外显子1，发现突变型亨廷顿蛋白导致大脑中出现年龄依赖性的亨廷顿蛋白 - PQ聚集，并可能导致突触蛋白缺失。为了确定这种神经元功能障碍是否导致外周功能障碍，我们进行了负趋地性试验以测量运动能力，发现神经元突变型亨廷顿蛋白导致运动能力出现年龄依赖性下降。接下来，我们发现雷帕霉素可减少大脑中的亨廷顿蛋白 - PQ聚集。这些结果证明了神经元中的亨廷顿蛋白 - PQ在HD模型中的功能障碍中的作用，表明脑 - 外周的相互作用可能对HD的发病机制很重要，并显示雷帕霉素可减少大脑中突变型亨廷顿蛋白的聚集。
Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.
登录
查看更多内容
影响因子：
7.4
作者：
Cortes, Constanza J.;La Spada, Albert R.
通讯作者：
La Spada, Albert R.
影响因子：
13.3
作者：
Bailus BJ;Scheeler SM;Simons J;Sanchez MA;Tshilenge KT;Creus-Muncunill J;Naphade S;Lopez-Ramirez A;Zhang N;Lakshika Madushani K;Moroz S;Loureiro A;Schreiber KH;Hausch F;Kennedy BK;Ehrlich ME;Ellerby LM
通讯作者：
Ellerby LM
影响因子：
7.7
作者：
Ehlen, J. Christopher;Brager, Allison J.;Paul, Ketema N.
通讯作者：
Paul, Ketema N.
影响因子：
4.8
作者：
Das, Falguni;Ghosh-Choudhury, Nandini;Choudhury, Goutam Ghosh
通讯作者：
Choudhury, Goutam Ghosh
影响因子：
13.1
作者：
Chuang CL;Demontis F
通讯作者：
Demontis F