ArticleHuman molecular genetics2019
Acute manganese treatment restores defective autophagic cargo loading in Huntington's disease cell lines.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 24 citations in OpenAlex.
- The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity.Neurotoxicity research · 2025Review
- Navigating the Autophagy Maze: ATG and Their Impact on Neurodegenerative Diseases.Molecular neurobiology · 2025Review
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Review
- Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.International journal of molecular sciences · 2023Article
- Alterations in metal homeostasis occur prior to canonical markers in Huntington disease.Scientific reports · 2022Article
- Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies.Frontiers in pharmacology · 2022Review
- YAC128 mouse model of Huntington disease is protected against subtle chronic manganese (Mn)-induced behavioral and neuropathological changes.Neurotoxicology · 2021Article
- Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity.Biomolecules · 2021Review
- Review
- Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update.International journal of molecular sciences · 2021Review
- The Impact of Environmental Factors on Monogenic Mendelian Diseases.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Identification of Three Small Molecules That Can Selectively Influence Cellular Manganese Levels in a Mouse Striatal Cell Model.Molecules (Basel, Switzerland) · 2021Article
- Manganese-induced neurodegenerative diseases and possible therapeutic approaches.Expert review of neurotherapeutics · 2020Review
- The impact of manganese on neurotransmitter systems.Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2020Review
- Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice.Metallomics : integrated biometal science · 2020Article
- The Role of Autophagy in Manganese-Induced Neurotoxicity.Frontiers in neuroscience · 2020Review
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
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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