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Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-function C9ORF72 ALS/FTD disease processes in vivo

View ORCID ProfileK. A. Staats, C. Seah, A. Sahimi, Y. Wang, N. Koutsodendris, S. Lin, D. Kim, W-H. Chang, K. A. Gray, Y. Shi, Y. Li, M. Chateau, V. R. Vangoor, K. Senthilkumar, R. J. Pasterkamp, P. Cannon, B.V. Zlokovic, J. K. Ichida
doi: https://doi.org/10.1101/685800
K. A. Staats
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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  • ORCID record for K. A. Staats
C. Seah
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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A. Sahimi
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Y. Wang
2Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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N. Koutsodendris
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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S. Lin
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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D. Kim
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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W-H. Chang
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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K. A. Gray
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Y. Shi
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Y. Li
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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M. Chateau
3Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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V. R. Vangoor
4Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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K. Senthilkumar
4Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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R. J. Pasterkamp
4Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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P. Cannon
3Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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B.V. Zlokovic
2Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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J. K. Ichida
1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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  • For correspondence: Ichida@usc.edu
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Abstract

The most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) in C9ORF72 that contributes to neurodegeneration by both loss-of-function (decreased C9ORF72 protein levels) and gain-of-function (e.g. dipeptide repeat protein production) mechanisms. Although therapeutics targeting the gain-of-function mechanisms are in clinical development, it is unclear if these will be efficacious given the contribution of C9ORF72 loss-of-function processes to neurodegeneration. Moreover, there is a lack of therapeutic strategies for C9ORF72 ALS/FTD with demonstrated efficacy in vivo. Here, we show that small molecule inhibition of PIKFYVE kinase rescues both loss- and gain-of-function C9ORF72 disease mechanisms in vivo. We find that the reduction of C9ORF72 in mouse motor neurons leads to a decrease in early endosomes. In contrast, treatment with the PIKFYVE inhibitor apilimod increases the number of endosomes and lysosomes. We show that reduced C9ORF72 levels increases glutamate receptor levels in hippocampal neurons in mice, and that apilimod treatment rescues this excitotoxicity-related phenotype in vivo. Finally, we show that apilimod also alleviates the gain-of-function pathology induced by the C9ORF72 HRE by decreasing levels of dipeptide repeat proteins derived from both sense and antisense C9ORF72 transcripts in hippocampal neurons in vivo. Our data demonstrate the neuroprotective effect of PIKFYVE kinase inhibition in both gain- and loss-of-function murine models of C9ORF72 ALS/FTD.

Footnotes

  • Staats, K. A. Kim.Staats.Work{at}gmail.com, Seah C. cseah{at}usc.edu, Sahimi, A. asahimi{at}usc.edu, Wang, Y. yaomingw{at}usc.edu, Koutsodendris, N. nkoutsodendris{at}gmail.com, Lin, S. shaoyuli{at}usc.edu, Kim, D. david.k.2015{at}gmail.com, Chang, W-H. wchang{at}acurastem.com, Gray, K. A. kag262{at}georgetown.edu, Shi, Y. shiyingxiao{at}gmail.com, Li, Y. yichen.li{at}st-annes.ox.ac.uk, Chateau, M. mchateau{at}usc.edu, Vangoor, V. R. V.Vangoor{at}umcutrecht.nl, Senthilkumar, K. K.Senthilkumar-2{at}umcutrecht.nl, Pasterkamp, R. J. R.J.Pasterkamp{at}umcutrecht.nl, Cannon, P. PCannon{at}usc.edu, Zlokovic, B.V. Zlokovic{at}usc.edu, Ichida, J. K. Ichida{at}usc.edu

  • List of abbreviations

    ALS
    amyotrophic lateral sclerosis
    CA
    Cornu Ammonis
    C9-ALS/FTD
    C9orf72 ALS/FTD
    C9-BAC mice
    C9orf72 containing 100-1000 GGGGCC repeats mice
    DG
    dentate gyrus
    DPR
    dipeptide repeat protein
    EEA1
    Early Endosome Antigen 1
    FTD
    frontotemporal dementia
    GP
    glycine-proline repeat DPR
    GR
    glycine-arginine repeat DPR
    HRE
    hexanucleotide repeat expansion
    HRP
    horseradish peroxidase
    iPSC
    induced pluripotent stem cell
    iMN
    induced motor neuron
    LAMP1
    Lysosomal Associated Membrane Protein 1
    NMDA
    N-methyl-D-aspartate
    PBS
    phosphate buffered saline
    PI5K
    Phosphatidylinositol 5-kinase
    PR
    proline-arginine repeat DPR
    RAN
    repeat-associated non-AUG
  • Copyright 
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    Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-function C9ORF72 ALS/FTD disease processes in vivo
    K. A. Staats, C. Seah, A. Sahimi, Y. Wang, N. Koutsodendris, S. Lin, D. Kim, W-H. Chang, K. A. Gray, Y. Shi, Y. Li, M. Chateau, V. R. Vangoor, K. Senthilkumar, R. J. Pasterkamp, P. Cannon, B.V. Zlokovic, J. K. Ichida
    bioRxiv 685800; doi: https://doi.org/10.1101/685800
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    Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-function C9ORF72 ALS/FTD disease processes in vivo
    K. A. Staats, C. Seah, A. Sahimi, Y. Wang, N. Koutsodendris, S. Lin, D. Kim, W-H. Chang, K. A. Gray, Y. Shi, Y. Li, M. Chateau, V. R. Vangoor, K. Senthilkumar, R. J. Pasterkamp, P. Cannon, B.V. Zlokovic, J. K. Ichida
    bioRxiv 685800; doi: https://doi.org/10.1101/685800

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