title: Inhibition of PIKfyve by YM-201636 dysregulates autophagy and leads to apoptosis-independent neuronal cell death.
abstract: The lipid phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2), 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)P 2, 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 apoptosis-independent 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.
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Martin
authors.forename: Callista B
authors.initials: CB
authors.lastname: Harper
authors.forename: Linda M
authors.initials: LM
authors.lastname: May
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Coulson
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Meunier
authors.forename: Shona L
authors.initials: SL
authors.lastname: Osborne
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055099:Neuroendocrine Cells / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D006575:Heterocyclic Compounds, 3-Ring; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C540576:6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide; C116930:Pikfyve protein, mouse
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