美国国立卫生研究院Juan S. Bonifacino研究组在研究中取得进展。他们发现溶酶体囊泡上的信使RNA转运可维持轴突线粒体稳态并防止轴突退化。相关论文发表在2024年4月10日出版的《自然-神经科学》杂志上。

在本研究中，研究人员通过敲除溶酶体-驱动蛋白适配体BLOC-one-related complex(BORC)来阻止这些囊泡进入轴突，从而鉴定了依赖溶酶体相关囊泡运输的轴突mRNA子集。研究发现，BORC基因敲除会导致一大群轴突mRNA的耗竭，这些mRNA主要编码核糖体和线粒体/氧化磷酸化相关蛋白。

这种损耗导致线粒体功能缺陷，并最终导致人诱导多能干细胞（iPSC）衍生轴突和小鼠神经元的退化。对耗竭mRNA通路的分析表明，BORC缺乏与常见的神经退行性疾病存在机理上的联系。这些结果表明，溶酶体相关囊泡上mRNA的转运对维持轴突稳态至关重要，其失效会导致轴突变性。

据悉，在神经元中，RNA颗粒沿轴突运输，以便在远离体节的地方进行翻译。最近的研究表明，这种运输部分涉及RNA颗粒搭溶酶体相关囊泡的便车。

附：英文原文

Title: Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration

Author: De Pace, Raffaella, Ghosh, Saikat, Ryan, Veronica H., Sohn, Mira, Jarnik, Michal, Rezvan Sangsari, Paniz, Morgan, Nicole Y., Dale, Ryan K., Ward, Michael E., Bonifacino, Juan S.

Issue&Volume: 2024-04-10

Abstract: In neurons, RNA granules are transported along the axon for local translation away from the soma. Recent studies indicate that some of this transport involves hitchhiking of RNA granules on lysosome-related vesicles. In the present study, we leveraged the ability to prevent transport of these vesicles into the axon by knockout of the lysosome–kinesin adaptor BLOC-one-related complex (BORC) to identify a subset of axonal mRNAs that depend on lysosome-related vesicles for transport. We found that BORC knockout causes depletion of a large group of axonal mRNAs mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This depletion results in mitochondrial defects and eventually leads to axonal degeneration in human induced pluripotent stem cell (iPSC)-derived and mouse neurons. Pathway analyses of the depleted mRNAs revealed a mechanistic connection of BORC deficiency with common neurodegenerative disorders. These results demonstrate that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration.

DOI: 10.1038/s41593-024-01619-1

Source: https://www.nature.com/articles/s41593-024-01619-1