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OptoGranules reveal the evolution of stress granules to ALS-FTD pathology

Peipei Zhang, Baochang Fan, Peiguo Yang, Jamshid Temirov, James Messing, Hong Joo Kim, J. Paul Taylor
doi: https://doi.org/10.1101/348870
Peipei Zhang
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
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Baochang Fan
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
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Peiguo Yang
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
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Jamshid Temirov
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
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James Messing
2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
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Hong Joo Kim
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
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J. Paul Taylor
1Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA
2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
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Abstract

Stress granules are non-membranous assemblies of mRNA and protein that form in response to a variety of stressors. Genetic, pathologic, biophysical and cell biological studies have implicated disturbances in the dynamics of membrane-less organelles, such as stress granules, as a pathobiological component of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)1–12. This confluence of evidence has inspired the hypothesis that these diseases reflect an underlying disturbance in the dynamics and material properties of stress granules; however, this concept has remained largely untestable in available models of stress granule assembly, which require the confounding variable of exogenous stressors. Here we demonstrate the development and use of a light-inducible stress granule system, termed OptoGranules, which permits discrete, experimental control of the dynamics and material properties of stress granules in living cells in the absence of exogenous stressors. The nucleator in this system is Opto-G3BP1, a light-sensitive chimeric protein assembled from the intrinsically disordered region (IDR) and RNA-binding domain of G3BP1 combined with the light-sensitive oligomerization domain of Arabidopsis thaliana cryptochrome 2 (CRY2) photolyase homology region (PHR). Upon stimulation with blue light, Opto-G3BP1 initiates the rapid assembly of dynamic, cytoplasmic, liquid granules that are composed of canonical stress granule components, including G3BP1, PABP, TIA1, TIAR, eIF4G, eIF3η, ataxin 2, GLE1, TDP-43 and polyadenylated RNA. With this system, we demonstrate that persistent or repetitive assembly of stress granules is cytotoxic and is accompanied by the evolution of stress granules to neuronal cytoplasmic inclusions that recapitulate the pathology of ALS-FTD.

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Posted June 15, 2018.
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OptoGranules reveal the evolution of stress granules to ALS-FTD pathology
Peipei Zhang, Baochang Fan, Peiguo Yang, Jamshid Temirov, James Messing, Hong Joo Kim, J. Paul Taylor
bioRxiv 348870; doi: https://doi.org/10.1101/348870
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OptoGranules reveal the evolution of stress granules to ALS-FTD pathology
Peipei Zhang, Baochang Fan, Peiguo Yang, Jamshid Temirov, James Messing, Hong Joo Kim, J. Paul Taylor
bioRxiv 348870; doi: https://doi.org/10.1101/348870

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