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Translational control in brain pathologies: biological significance and therapeutic opportunities

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Abstract

Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system. In this review, we provide a brief overview of the basic principles of mRNA translation, and discuss alterations of this process relevant to CNS disease conditions, with a focus on brain tumors and chronic neurological conditions. Finally, synthesizing this knowledge, we discuss the opportunities to exploit the biology of altered mRNA translation for novel therapies in brain disorders, as well as how studying these alterations can shed new light on disease mechanisms.

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Funding

This work was partially supported by Canadian Cancer Society Research Institute (CCSRI) Impact Grant (Grant #703205; to PHS), and CIHR Foundation Grant FDN-143280 (to PHS). AD is supported by a Harry and Florence Dennison Fellowship in Medical Research, 4 Year Fellowship, and a Killam Doctoral Scholarship from the University of British Columbia, BC, Canada. Funding to AJ was in the form of an AIAS-COFUND fellowship from European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie agreement (Grant #754513) and the Lundbeckfonden, Denmark (Grant #R250-2017-1131).

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Authors and Affiliations

  1. Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada

    Alberto Delaidelli & Poul H. Sorensen

  2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

    Alberto Delaidelli & Poul H. Sorensen

  3. Department of Biomedicine, Aarhus Institute of Advanced Studies, Aarhus University, Høegh-Guldbergs Gade 6B, 8000, Aarhus C, Denmark

    Asad Jan

  4. Department for Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Jochen Herms

  5. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany

    Jochen Herms

  6. Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, Schillerstraße 44, 80336, Munich, Germany

    Jochen Herms

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  1. Alberto Delaidelli
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  2. Asad Jan
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Delaidelli, A., Jan, A., Herms, J. et al. Translational control in brain pathologies: biological significance and therapeutic opportunities. Acta Neuropathol 137, 535–555 (2019). https://doi.org/10.1007/s00401-019-01971-8

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