TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons
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ORIGINAL PAPER
TDP‑43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons Seiichi Nagano1,2 · Junki Jinno2 · Rehab F. Abdelhamid2 · Yinshi Jin2,3 · Megumi Shibata1 · Shohei Watanabe1 · Sachiko Hirokawa4 · Masatoyo Nishizawa5 · Kenji Sakimura6 · Osamu Onodera5 · Hironori Okada7 · Takashi Okada8 · Yuko Saito9 · Junko Takahashi‑Fujigasaki10 · Shigeo Murayama10 · Shuji Wakatsuki1 · Hideki Mochizuki2 · Toshiyuki Araki1 Received: 30 March 2020 / Revised: 1 August 2020 / Accepted: 1 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5′ untranslated region, which contains a common 5′ terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy. Keywords Ribonucleic acid · Local translation · Ribosome · Amyotrophic lateral sclerosis Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02205-y) contains supplementary material, which is available to authorized users. * Seiichi Nagano [email protected]‑u.ac.jp
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Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan
* Toshiyuki Araki [email protected]
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Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
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Department of P
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