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bioRxiv · 10.1101/2021.01.21.427704

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

See, S. K.·Chen, M.·Bax, S.·Tian, R.·Woerman, A.·Tse, E.·Johnson, I. E.·Nowotny, C.·Munoz, E. N.·Sengstack, J.·Southworth, D. R.·Gestwicki, J. E.·Leonetti, M. D.·Kampmann, M.
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Abstract

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

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See, S. K., Chen, M., Bax, S., Tian, R., Woerman, A., Tse, E., Johnson, I. E., Nowotny, C., Munoz, E. N., Sengstack, J., Southworth, D. R., Gestwicki, J. E., Leonetti, M. D., Kampmann, M.. 2021-01-22. PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation. https://doi.org/10.1101/2021.01.21.427704

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