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溶酶体囊泡上的信使 RNA 转运维持轴突线粒体的动态平衡，防止轴突变性。

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

机构信息

Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

出版信息

Nat Neurosci. 2024 Jun;27(6):1087-1102. doi: 10.1038/s41593-024-01619-1. Epub 2024 Apr 10.

DOI:10.1038/s41593-024-01619-1
PMID:38600167
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11156585/
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.

摘要

在神经元中，RNA 颗粒沿着轴突运输，以便在远离胞体的地方进行局部翻译。最近的研究表明，这种运输的一部分涉及 RNA 颗粒搭溶酶体相关小泡的便车。在本研究中，我们利用破坏溶酶体-驱动蛋白衔接物 BLOC-one 相关复合物 (BORC) 来阻止这些小泡进入轴突的能力，从而鉴定出一组依赖溶酶体相关小泡进行运输的轴突 mRNA。我们发现 BORC 敲除导致一大组主要编码核糖体和线粒体/氧化磷酸化蛋白的轴突 mRNA 耗竭。这种耗竭导致线粒体缺陷，最终导致人诱导多能干细胞 (iPSC) 衍生和小鼠神经元中的轴突退化。耗竭 mRNA 的通路分析显示 BORC 缺陷与常见神经退行性疾病之间存在机制联系。这些结果表明，溶酶体相关小泡上的 mRNA 运输对于维持轴突内稳态至关重要，其失败会导致轴突退化。

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