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Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning & reduces neurodegeneration

Veronica H. Ryan, Theodora Myrto Perdikari, Mandar T. Naik, Camillo F. Saueressig, Jeremy Lins, View ORCID ProfileGregory L. Dignon, View ORCID ProfileJeetain Mittal, Anne C. Hart, View ORCID ProfileNicolas L. Fawzi
doi: https://doi.org/10.1101/2020.03.15.992768
Veronica H. Ryan
1Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA
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Theodora Myrto Perdikari
2Biomedical Engineering Graduate Program, Brown University, Providence, RI 02912, USA
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Mandar T. Naik
3Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA
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Camillo F. Saueressig
4Department of Neuroscience, Brown University, Providence, RI 02912, USA
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Jeremy Lins
4Department of Neuroscience, Brown University, Providence, RI 02912, USA
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Gregory L. Dignon
5Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA
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  • ORCID record for Gregory L. Dignon
Jeetain Mittal
5Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA
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Anne C. Hart
4Department of Neuroscience, Brown University, Providence, RI 02912, USA
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  • For correspondence: nicolas_fawzi@brown.edu anne_hart@brown.edu
Nicolas L. Fawzi
3Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA
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  • ORCID record for Nicolas L. Fawzi
  • For correspondence: nicolas_fawzi@brown.edu anne_hart@brown.edu
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Summary

mRNA transport in neurons is a ubiquitous process but has been often overlooked as a contributor to disease. Mutations of transport granule protein hnRNPA2 cause hereditary proteinopathy of neurons, myocytes, and bone. Here, we examine transport granule component specificity, assembly/disassembly, and the link to neurodegeneration. hnRNPA2 transport granule components hnRNPF and ch-TOG interact weakly with hnRNPA2 yet they each partition specifically into hnRNPA2 liquid phases. hnRNPA2 tyrosine phosphorylation dissociates granule interactions by reducing hnRNPA2 phase separation and preventing partitioning of hnRNPF and ch-TOG; tyrosine phosphorylation also decreases aggregation of hnRNPA2 disease mutants. A C. elegans model of hnRNPA2 D290V-associated neurodegeneration exhibits TDP-43 ortholog-dependent glutamatergic neurodegeneration. Expression of the tyrosine kinase that phosphorylates hnRNPA2 reduces glutamatergic neurodegeneration. The evidence for specific partitioning of granule components as well as disruption of these interactions and reduction of neurodegeneration by tyrosine phosphorylation suggest transport granule biology has a role in the pathogenesis of neurodegeneration.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 18, 2020.
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Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning & reduces neurodegeneration
Veronica H. Ryan, Theodora Myrto Perdikari, Mandar T. Naik, Camillo F. Saueressig, Jeremy Lins, Gregory L. Dignon, Jeetain Mittal, Anne C. Hart, Nicolas L. Fawzi
bioRxiv 2020.03.15.992768; doi: https://doi.org/10.1101/2020.03.15.992768
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Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning & reduces neurodegeneration
Veronica H. Ryan, Theodora Myrto Perdikari, Mandar T. Naik, Camillo F. Saueressig, Jeremy Lins, Gregory L. Dignon, Jeetain Mittal, Anne C. Hart, Nicolas L. Fawzi
bioRxiv 2020.03.15.992768; doi: https://doi.org/10.1101/2020.03.15.992768

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