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Sidibé H, Khalfallah Y, Xiao S, et al. TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia. Brain. 2021;144(11):3461-3476doi: 10.1093/brain/awab217.
Sidibé, H., Khalfallah, Y., Xiao, S., Gómez, N. B., Fakim, H., Tank, E. M. H., Di Tomasso, G., Bareke, E., Aulas, A., McKeever, P. M., Melamed, Z., Destroimaisons, L., Deshaies, J. E., Zinman, L., Parker, J. A., Legault, P., Tétreault, M., Barmada, S. J., Robertson, J., & Vande Velde, C. (2021). TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia. Brain : a journal of neurology, 144(11), 3461-3476. https://doi.org/10.1093/brain/awab217
Sidibé, Hadjara, et al. "TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia." Brain : a journal of neurology vol. 144,11 (2021): 3461-3476. doi: https://doi.org/10.1093/brain/awab217
Sidibé H, Khalfallah Y, Xiao S, Gómez NB, Fakim H, Tank EMH, Di Tomasso G, Bareke E, Aulas A, McKeever PM, Melamed Z, Destroimaisons L, Deshaies JE, Zinman L, Parker JA, Legault P, Tétreault M, Barmada SJ, Robertson J, Vande Velde C. TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia. Brain. 2021 Dec 16;144(11):3461-3476. doi: 10.1093/brain/awab217. PMID: 34115105; PMCID: PMC8677511.
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Brain. 2021 Dec 16;144(11):3461-3476. doi: 10.1093/brain/awab217.

TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia.

Brain : a journal of neurology

Hadjara Sidibé, Yousra Khalfallah, Shangxi Xiao, Nicolás B Gómez, Hana Fakim, Elizabeth M H Tank, Geneviève Di Tomasso, Eric Bareke, Anaïs Aulas, Paul M McKeever, Ze'ev Melamed, Laurie Destroimaisons, Jade-Emmanuelle Deshaies, Lorne Zinman, J Alex Parker, Pascale Legault, Martine Tétreault, Sami J Barmada, Janice Robertson, Christine Vande Velde

Affiliations

  1. Department of Neurosciences, Université de Montréal, Montréal, QC H3A 0E8, Canada.
  2. CHUM Research Center, Montréal, QC H2X 0A9, Canada.
  3. Department of Biochemistry, Université de Montréal, Montréal, QC H3A 0E8, Canada.
  4. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 0S8, Canada.
  5. Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
  6. Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA.
  7. University of California, San Diego/Ludwig Institute for Cancer Research, San Diego, CA 92093, USA.
  8. Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada.
  9. Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 34115105 PMCID: PMC8677511 DOI: 10.1093/brain/awab217

Abstract

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3' untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Keywords: G3BP1; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; stress granules

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