YAC128 mouse model of Huntington disease is protected against subtle chronic manganese (Mn)-induced behavioral and neuropathological changes

Wilcox, Jordyn M.; Pfalzer, Anna C; Tienda, Adriana; Debbiche, Ines F.; Cox, Ellen C.; Totten, Melissa; Erikson, Keith M.; Harrison, Fiona E.; Bowman, Aaron B.

doi:10.1016/j.neuro.2021.09.002

Cited by 8 publications

(3 citation statements)

References 57 publications

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“…Mn exposure can also correct abnormalities in the striatal urea cycle in HD rodents 12 . We also observe global suppression of transcriptomic and metabolomic response to Mn in the same rodent model 13,14 -suggesting impairments in Mn tra cking in HD. Iron also accumulates in post-mortem HD brains as well as in HD animal models 2 .…”

Section: Introductionmentioning

confidence: 58%

Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Pfalzer

Yan

Kang

et al. 2021

Preprint

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Objective: The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients.Methods: Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples.Results: We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage.Interpretation: These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

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Section: Introductionmentioning

confidence: 58%

Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Pfalzer

Yan

Kang

et al. 2021

Preprint

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show abstract

“…Mn exposure can also correct abnormalities in the striatal urea cycle in HD rodents 12 . We also observe global suppression of transcriptomic and metabolomic response to Mn in the same rodent model 13 , 14 —suggesting impairments in Mn trafficking in HD. Iron also accumulates in post-mortem HD brains as well as in HD animal models 2 .…”

Section: Introductionmentioning

confidence: 59%

Alterations in metal homeostasis occur prior to canonical markers in Huntington disease

Pfalzer

Yan

Kang

et al. 2022

Sci Rep

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The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients. Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples. We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage. These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

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“…In addition, autophagy, as a key downstream degradation pathway, has been increasingly valued for its role in Mn neurotoxicity. In contrast to previous short-term high-dose Mn exposure models, recent studies have adopted low-dose long-term Mn exposures [189][190][191][192], attempting to design experimental exposure models that mimic actual human exposure and better characterize the mechanism of Mn-induced health effects in humans.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathways Involved in Manganese-Induced Neurotoxicity

Cheng,

Villahoz,

Ponzio

et al. 2023

Cells

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Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP–AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

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YAC128 mouse model of Huntington disease is protected against subtle chronic manganese (Mn)-induced behavioral and neuropathological changes

Cited by 8 publications

References 57 publications

Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Alterations in metal homeostasis occur prior to canonical markers in Huntington disease

Signaling Pathways Involved in Manganese-Induced Neurotoxicity

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