Mitochondrial membranes modify mutant huntingtin aggregation.
Mitochondrial membranes modify mutant huntingtin aggregation.
复制标题
DOI：
10.1016/j.bbamem.2021.183663
复制
发表时间：
2021-10-01
期刊：
影响因子：
--
通讯作者：
Legleiter J
中科院分区：
文献类型：
--
作者：
Adegbuyiro A;Sedighi F;Jain P;Pinti MV;Siriwardhana C;Hollander JM;Legleiter J
亨廷顿氏病（HD）是由亨廷顿（htt）蛋白N-末端附近的多聚谷氨酰胺（polyQ）束扩张引起的神经退行性疾病。扩张的polyQ束易于聚集成低聚物和不溶性原纤维。突变体htt（mhtt）定位于各种细胞器，包括线粒体。具体而言，在HD中观察到线粒体缺陷、形态学改变和功能障碍。线粒体脂质，特别是心磷脂（CL），在线粒体功能中是必不可少的，并有可能直接与htt相互作用，改变其聚集。在这里，线粒体膜对htt聚集的影响进行了研究，使用线粒体膜模拟物和组织来源的富含线粒体的组分的组合。探索了外线粒体膜模拟物和内线粒体膜模拟物（分别为OMM和IMM）暴露于mhtt的影响。OMM和IMM降低了mhtt絮凝，IMM具有更大的影响。CL在mhtt聚集中的作用进行了研究，使用一个简单的PC系统与不同摩尔比的CL。较低的CL摩尔比（<5%）促进了纤维化;然而，增加CL含量阻碍了纤维化。正如原位原子力显微镜所揭示的那样，与IMM模拟物相比，OMM模拟物表面的mhtt聚集和相关的膜形态变化显着不同。虽然在OMM上观察到具有少量纤维状聚集体的mhtt的球形沉积物，但在IMM上观察到平台样结构域。在暴露于纯化的富含丝氨酸的级分的情况下观察到对htt聚集的类似影响。总的来说，这些观察结果表明线粒体膜严重影响htt聚集，从而影响HD。
Huntington’s disease (HD) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ tracts are prone to aggregate into oligomers and insoluble fibrils. Mutant htt (mhtt) localizes to variety of organelles, including mitochondria. Specifically, mitochondrial defects, morphological alteration, and dysfunction are observed in HD. Mitochondrial lipids, cardiolipin (CL) in particular, are essential in mitochondria function and have the potential to directly interact with htt, altering its aggregation. Here, the impact of mitochondrial membranes on htt aggregation was investigated using a combination of mitochondrial membrane mimics and tissue-derived mitochondrial-enriched fractions. The impact of exposure of outer and inner mitochondrial membrane mimics (OMM and IMM respectively) to mhtt was explored. OMM and IMM reduced mhtt fibrillization, with IMM having a larger effect. The role of CL in mhtt aggregation was investigated using a simple PC system with varying molar ratios of CL. Lower molar ratios of CL (<5%) promoted fibrillization; however, increased CL content retarded fibrillization. As revealed by in situ AFM, mhtt aggregation and associated membrane morphological changes at the surface of OMM mimics was markedly different compared to IMM mimics. While globular deposits of mhtt with few fibrillar aggregates were observed on OMM, plateau-like domains were observed on IMM. A similar impact on htt aggregation was observed with exposure to purified mitochondrial-enriched fractions. Collectively, these observations suggest mitochondrial membranes heavily influence htt aggregation with implication for HD.
登录
查看更多内容
影响因子：
3.5
作者：
Basu Ball W;Neff JK;Gohil VM
通讯作者：
Gohil VM
影响因子：
4.7
作者：
Frohman, Michael A.
通讯作者：
Frohman, Michael A.
DOI：
10.1007/978-3-319-71779-1_3
发表时间：
2018-01-01
期刊：
POLYGLUTAMINE DISORDERS
影响因子：
--
作者：
Carmo, Catarina;Naia, Luana;Cristina Rego, A.
通讯作者：
Cristina Rego, A.
影响因子：
6.1
作者：
Cherubini, Marta;Lopez-Molina, Laura;Gines, Silvia
通讯作者：
Gines, Silvia
影响因子：
2.9
作者：
Chaibva, Maxmore;Burke, Kathleen A.;Legleiter, Justin
通讯作者：
Legleiter, Justin