PT  - JOURNAL ARTICLE
AU  - Stephanie K. See
AU  - Merissa Chen
AU  - Sophie Bax
AU  - Ruilin Tian
AU  - Amanda Woerman
AU  - Eric Tse
AU  - Isabel E. Johnson
AU  - Carlos Nowotny
AU  - Elise N. Muñoz
AU  - Janine Sengstack
AU  - Daniel R. Southworth
AU  - Jason E. Gestwicki
AU  - Manuel D. Leonetti
AU  - Martin Kampmann
TI  - PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation
AID  - 10.1101/2021.01.21.427704
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.21.427704
4099  - http://biorxiv.org/content/early/2021/01/22/2021.01.21.427704.short
4100  - http://biorxiv.org/content/early/2021/01/22/2021.01.21.427704.full
AB  - 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 StatementThe authors have declared no competing interest.