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Publication
Acute manganese treatment restores defective autophagic cargo loading in
Huntington's disease cell lines.
Authors Bryan MR, O'Brien MT, Nordham KD, Rose DIR, Foshage AM, Joshi P, Nitin R, Uhouse
MA, Di Pardo A, Zhang Z, Maglione V, Aschner M, Bowman AB
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Human molecular genetics
Year 2019
Date Published 11/1/2019
Volume : Pages 28 : 3825 - 3841
PubMed Reference 31600787
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.




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