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Comment
. 2023 Nov;39(11):1738-1740.
doi: 10.1007/s12264-023-01113-x. Epub 2023 Sep 9.

PIKFYVE Inhibition, A Neuronal "Emetic" for Treating ALS?

Wenkai Yue  1   2 , Connie W Tang  3 , Yanshan Fang  4   5
Affiliations
Comment

PIKFYVE Inhibition, A Neuronal "Emetic" for Treating ALS?

Wenkai Yue et al. Neurosci Bull. 2023 Nov.
No abstract available

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
PIKFYVE inhibition promotes unconventional clearance of pathological proteins via exocytosis and mitigates disease in diverse models of ALS. A, B Suppression of the PIKFYVE kinase by a small-molecule inhibitor apilimod or antisense oligonucleotides (ASOs) activates protein clearance independent of its role in the autophagy pathway (A) and instead primarily mediated via exocytosis, in which amphisomes and multivesicular bodies (MVBs) containing aggregation-prone, pathological proteins, such as phosphorylated TDP-43 (pTDP-43) and dipeptide repeat proteins (DRPs), are “vomited” out of neurons (B). C PIKFYVE inhibition ameliorates neurodegeneration in induced motor neurons (iMNs) derived from patients either carrying mutations in C9ORF72, TARDBP, FUS, or with sporadic ALS and extends the lifespan of multiple animal models of ALS, including C. elegans, Drosophila, and mouse. As such, activation of the unconventional protein clearance pathway of exocytosis by PIKFYVE inhibition provides a promising therapeutic candidate with broad efficacy for the treatment of ALS.
See this image and copyright information in PMC

Comment on

  • Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
    Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng TY, Lee SJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, van den Berg LH, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK. Shi Y, et al. Nat Med. 2018 Mar;24(3):313-325. doi: 10.1038/nm.4490. Epub 2018 Feb 5. Nat Med. 2018. PMID: 29400714 Free PMC article.

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