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.

在神经元中，RNA 颗粒沿着轴突运输，进行局部翻译远离胞体。最近的研究表明，这种运输的一部分涉及 RNA 颗粒在溶酶体相关囊泡上的搭便车。在本研究中，我们利用通过敲除溶酶体-驱动蛋白接头BLOC-one相关复合物（BORC）来阻止这些囊泡转运到轴突中的能力来鉴定依赖于溶酶体相关囊泡的轴突mRNA子集。运输。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 的消耗。这种耗竭会导致线粒体缺陷，并最终导致人类诱导多能干细胞 (iPSC) 来源的神经元和小鼠神经元的轴突变性。对耗尽的 mRNA 的通路分析揭示了 BORC 缺陷与常见神经退行性疾病的机制联系。这些结果表明，溶酶体相关囊泡上的 mRNA 转运对于维持轴突稳态至关重要，其失败会导致轴突变性。