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PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation

Stephanie K. See, Merissa Chen, Sophie Bax, Ruilin Tian, Amanda Woerman, Eric Tse, Isabel E. Johnson, Carlos Nowotny, Elise N. Muñoz, Janine Sengstack, Daniel R. Southworth, Jason E. Gestwicki, Manuel D. Leonetti, View ORCID ProfileMartin Kampmann
doi: https://doi.org/10.1101/2021.01.21.427704
Stephanie K. See
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
2Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, CA 94158
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Merissa Chen
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
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Sophie Bax
3Chan Zuckerberg Biohub, San Francisco, California 94158
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Ruilin Tian
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
4Biophysics Graduate Program, University of California, San Francisco, San Francisco, CA 94158
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Amanda Woerman
5Institute for Applied Life Sciences and Department of Biology, University of Massachusetts, Amherst, Massachusetts 01003
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Eric Tse
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
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Isabel E. Johnson
6Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158
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Carlos Nowotny
6Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158
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Elise N. Muñoz
6Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158
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Janine Sengstack
6Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158
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Daniel R. Southworth
6Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158
7Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158
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Jason E. Gestwicki
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
8Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158
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Manuel D. Leonetti
3Chan Zuckerberg Biohub, San Francisco, California 94158
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Martin Kampmann
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158
3Chan Zuckerberg Biohub, San Francisco, California 94158
7Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158
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  • ORCID record for Martin Kampmann
  • For correspondence: martin.kampmann@ucsf.edu
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ABSTRACT

The inter-cellular prion-like propagation of α-synuclein aggregation is emerging as an important mechanism driving the progression of neurodegenerative diseases including Parkinson’s disease and multiple system atrophy (MSA). To discover therapeutic strategies reducing the spread of α-synuclein aggregation, we performed a genome-wide CRISPR interference screen in a human cell-based model. We discovered that inhibiting PIKfyve dramatically reduced α-synuclein aggregation induced with both recombinant α-synuclein fibrils and fibrils isolated from MSA patient brain. While PIKfyve inhibition did not affect fibril uptake or α-synuclein clearance or secretion, it reduced α-synuclein trafficking from the early endosome to the lysosome, thereby limiting fibril escape from the lysosome and reducing the amount of fibrils that reach cytosolic α-synuclein to induce aggregation. These findings point to the endolysosomal transport of fibrils as a critical step in the propagation of α-synuclein aggregation and a potential therapeutic target.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 4.0 International license.
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Posted January 22, 2021.
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PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation
Stephanie K. See, Merissa Chen, Sophie Bax, Ruilin Tian, Amanda Woerman, Eric Tse, Isabel E. Johnson, Carlos Nowotny, Elise N. Muñoz, Janine Sengstack, Daniel R. Southworth, Jason E. Gestwicki, Manuel D. Leonetti, Martin Kampmann
bioRxiv 2021.01.21.427704; doi: https://doi.org/10.1101/2021.01.21.427704
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PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation
Stephanie K. See, Merissa Chen, Sophie Bax, Ruilin Tian, Amanda Woerman, Eric Tse, Isabel E. Johnson, Carlos Nowotny, Elise N. Muñoz, Janine Sengstack, Daniel R. Southworth, Jason E. Gestwicki, Manuel D. Leonetti, Martin Kampmann
bioRxiv 2021.01.21.427704; doi: https://doi.org/10.1101/2021.01.21.427704

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