Dargan Rachael, Mikheenko Alla, Johnson Nicholas L, Packer Benjamin E, Li Ziyi, Craig Emma J, Como Christina N, Sarbanes Stephanie L, Bereda Colleen, Hao Ying, Mehta Puja R, Keuss Matthew, Nalls Mike A, Qi Yue A, Weller Cory A, Fratta Pietro, Ryan Veronica H
Center for Alzheimer's and Related Dementias, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, United States.
UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
Nucleic Acids Res. 2025 Jul 19;53(14). doi: 10.1093/nar/gkaf709.
Neurons rely on messenger RNA (mRNA) transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA-binding proteins (RBPs), including those associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP depletion on mRNA transport and local translation in induced pluripotent stem cell-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 induce distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to slightly increased neuritic mRNA and translation, while hnRNPA1 loss has more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.
神经元依靠信使核糖核酸（mRNA）运输和局部翻译，以促进在远离细胞体的区域快速合成蛋白质。这些过程允许对翻译进行精确的空间和时间控制，并由RNA结合蛋白（RBP）介导，包括那些与神经退行性疾病相关的蛋白。在这里，我们使用蛋白质组学、转录组学和显微镜技术来研究RBP缺失对诱导多能干细胞衍生神经元中mRNA运输和局部翻译的影响。我们发现数千种转录本在神经突中富集，并且其中许多转录本在局部进行翻译，这可能是由于神经突中转录本长度较短所致。额颞叶痴呆/肌萎缩侧索硬化症（FTD/ALS）相关的RBP TDP-43和hnRNPA1的缺失会在神经突蛋白质组和转录组中诱导不同的改变。TDP-43基因敲除（KD）导致神经突mRNA和翻译略有增加，而hnRNPA1的缺失对局部mRNA谱的影响较为温和，这可能是由于hnRNPA3的补偿作用。这些结果突出了FTD/ALS相关RBP在神经元mRNA运输和局部翻译中的关键作用，以及这些过程在神经元健康和疾病中的重要性。
