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Title: Acute manganese treatment restores defective autophagic cargo loading in Huntington's disease cell lines.

Authors: Bryan, Miles R; O'Brien, Michael T; Nordham, Kristen D; Rose, Daniel I R; Foshage, Audra M; Joshi, Piyush; Nitin, Rachana; Uhouse, Michael A; Di Pardo, Alba; Zhang, Ziyan; Maglione, Vittorio; Aschner, Michael; Bowman, Aaron B

Published In Hum Mol Genet, (2019 11 15)

Abstract: The molecular etiology linking the pathogenic mutations in the Huntingtin (Htt) gene with Huntington's disease (HD) is unknown. Prior work suggests a role for Htt in neuronal autophagic function and mutant HTT protein disrupts autophagic cargo loading. Reductions in the bioavailability of the essential metal manganese (Mn) are seen in models of HD. Excess cellular Mn impacts autophagic function, but the target and molecular basis of these changes are unknown. Thus, we sought to determine if changes in cellular Mn status impact autophagic processes in a wild-type or mutant Htt-dependent manner. We report that the HD genotype is associated with reduced Mn-induced autophagy and that acute Mn exposure increases autophagosome induction/formation. To determine if a deficit in bioavailable Mn is mechanistically linked to the autophagy-related HD cellular phenotypes, we examined autophagosomes by electron microscopy. We observed that a 24 h 100 uM Mn restoration treatment protocol attenuated an established HD 'cargo-recognition failure' in the STHdh HD model cells by increasing the percentage of filled autophagosomes. Mn restoration had no effect on HTT aggregate number, but a 72 h co-treatment with chloroquine (CQ) in GFP-72Q-expressing HEK293 cells increased the number of visible aggregates in a dose-dependent manner. As CQ prevents autophagic degradation this indicates that Mn restoration in HD cell models facilitates incorporation of aggregates into autophagosomes. Together, these findings suggest that defective Mn homeostasis in HD models is upstream of the impaired autophagic flux and provide proof-of-principle support for increasing bioavailable Mn in HD to restore autophagic function and promote aggregate clearance.

PubMed ID: 31600787 Exiting the NIEHS site

MeSH Terms: Animals; Autophagosomes/drug effects; Autophagosomes/metabolism; Autophagy/drug effects*; Cell Line; Disease Models, Animal; HEK293 Cells; Humans; Huntingtin Protein/metabolism; Huntingtin Protein/physiology; Huntington Disease/genetics; Huntington Disease/metabolism*; Huntington Disease/therapy; Induced Pluripotent Stem Cells; Manganese/metabolism; Manganese/pharmacology*; Mice; Microscopy, Electron/methods; Mutation; Neurons/metabolism

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Last Reviewed: October 07, 2024