RT Journal Article
SR Electronic
T1 PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.21.427704
DO 10.1101/2021.01.21.427704
A1 Stephanie K. See
A1 Merissa Chen
A1 Sophie Bax
A1 Ruilin Tian
A1 Amanda Woerman
A1 Eric Tse
A1 Isabel E. Johnson
A1 Carlos Nowotny
A1 Elise N. Muñoz
A1 Janine Sengstack
A1 Daniel R. Southworth
A1 Jason E. Gestwicki
A1 Manuel D. Leonetti
A1 Martin Kampmann
YR 2021
UL http://biorxiv.org/content/early/2021/01/22/2021.01.21.427704.abstract
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.