Inhibition of PIKfyve by YM-201636 Dysregulates Autophagy and Leads to Apoptosis-Independent Neuronal Cell Death

Martin, Sally, Harper, Callista B., May, Linda M., Coulson, Elizabeth J., Meunier, Frederic A. and Osborne, Shona L. (2013) Inhibition of PIKfyve by YM-201636 Dysregulates Autophagy and Leads to Apoptosis-Independent Neuronal Cell Death. PLoS One, 8 3: e60152.1-e60152.14. doi:10.1371/journal.pone.0060152

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Author Martin, Sally
Harper, Callista B.
May, Linda M.
Coulson, Elizabeth J.
Meunier, Frederic A.
Osborne, Shona L.
Title Inhibition of PIKfyve by YM-201636 Dysregulates Autophagy and Leads to Apoptosis-Independent Neuronal Cell Death
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-03
Sub-type Article (original research)
DOI 10.1371/journal.pone.0060152
Open Access Status DOI
Volume 8
Issue 3
Start page e60152.1
End page e60152.14
Total pages 14
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2014
Language eng
Formatted abstract
The lipid phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), synthesised by PIKfyve, regulates a number of intracellular membrane trafficking pathways. Genetic alteration of the PIKfyve complex, leading to even a mild reduction in PtdIns(3,5)P2,
results in marked neurodegeneration via an uncharacterised mechanism. In the present study we have shown that selectively inhibiting PIKfyve activity, using YM-201636, significantly reduces the survival of primary mouse hippocampal
neurons in culture. YM-201636 treatment promoted vacuolation of endolysosomal membranes followed by apoptosisindependent cell death. Many vacuoles contained intravacuolar membranes and inclusions reminiscent of autolysosomes.
Accordingly, YM-201636 treatment increased the level of the autophagosomal marker protein LC3-II, an effect that was potentiated by inhibition of lysosomal proteases, suggesting that alterations in autophagy could be a contributing factor to
neuronal cell death.
Keyword Causes Neurodegeneration
Endocytosed Receptors
Nervous system
Protein
Nerve cell culture
Lysosome enzyme
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 15 times in Scopus Article | Citations
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