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HMGB1 Mediates Inflammation-Induced DMT1 Increase and Dopaminergic Neurodegeneration in the Early Stage of Parkinsonism

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Abstract

Both neuroinflammation and iron accumulation play roles in the pathogenesis of Parkinson’s disease (PD). However, whether inflammation induces iron dyshomeostasis in dopaminergic neurons at an early stage of PD, at which no quantifiable dopaminergic neuron loss can be observed, is still unknown. As for the inflammation mediators, although several cytokines have been reported to increase in PD, the functions of these cytokines in the SN are double-edged and controversial. In this study, whether inflammation could induce iron dyshomeostasis in dopaminergic neurons through high mobility group protein B1 (HMGB1) in the early stage of PD is explored. Lipopolysaccharide (LPS), a toxin that primarily activates glia cells, and 6-hydroxydopamine (6-OHDA), the neurotoxin that firstly impacts dopaminergic neurons, were utilized to mimic PD in rats. We found a common and exceedingly early over-production of HMGB1, followed by an increase of divalent metal transporter 1 with iron responsive element (DMT1+) in the dopaminergic neurons before quantifiable neuronal loss. HMGB1 neutralizing antibody suppressed inflammation in the SN, DMT1+ elevation in dopaminergic neurons, and dopaminergic neuronal loss in both LPS and 6-OHDA administration- induced PD models. On the contrary, interleukin-1β inhibitor diacerein failed to suppress these outcomes induced by 6-OHDA. Our findings not only demonstrate that inflammation could be one of the causes of DMT1+ increase in dopaminergic neurons, but also highlight HMGB1 as a pivotal early mediator of inflammation-induced iron increase and subsequent neurodegeneration, thereby HMGB1 could serve as a potential target for early-stage PD treatment.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

DMT1+:

Divalent metal transporter 1 with iron responsive element

ED-1:

Anti-macrophages/monocytes antibody, clone ED-1

GFAAS:

Graphite furnace atomic absorption spectroscopy

GFAP:

Glial fibrillary acidic protein

HMGB1:

High mobility group protein B1

IBA1:

Ionized calcium-binding adaptor molecule 1

IL-1β:

Interleukin-1β

LPS:

Lipopolysaccharide

PD:

Parkinson’s disease

SN:

Substantia nigra

RAGE:

Receptor for advanced glycation end products

TNF-α:

Tumor necrosis factor-α

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Funding

This work was supported by the Hong Kong Research Grants Council-General Research Fund, 14115821, 14113522, Collaborative Research Fund, C4012-22GF, Health and Medical Research Fund, 7180906.

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Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, China

    Tuo Liang, Sheng-Xi Yang, Christopher Qian, Li-Da Du & Ya Ke

  2. Institute of Translational and Precision Medicine, Nantong University, Nantong, 226001, China

    Zhong-Ming Qian

  3. Department of Neuroscience, City University of Hong Kong, Hong Kong, China

    Wing-Ho Yung

Authors
  1. Tuo Liang
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  2. Sheng-Xi Yang
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  3. Christopher Qian
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  4. Li-Da Du
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  5. Zhong-Ming Qian
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  6. Wing-Ho Yung
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  7. Ya Ke
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Contributions

Y.K. conceived the project, designed the experiments, and supervised the project. W.H.Y. and Z.M.Q. designed the experiments, supervised the studies, and analyzed the data. T.L., S.X.Y., and L.D.D. designed the experiments, performed the experiments, analyzed the data, and prepared the figures. Y.K., C.Q., and T.L. wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ya Ke.

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Ethics Approval and Consent to Participate

The Animal Ethics and Experimentation Committee of the Chinese University of Hong Kong approved the use of animals for this study (Ref No. 14-068-GRF), and all experiments follow the relevant regulatory standards.

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Not applicable.

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The authors declare no competing interests.

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Liang, T., Yang, SX., Qian, C. et al. HMGB1 Mediates Inflammation-Induced DMT1 Increase and Dopaminergic Neurodegeneration in the Early Stage of Parkinsonism. Mol Neurobiol 61, 2006–2020 (2024). https://doi.org/10.1007/s12035-023-03668-2

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  • DOI: https://doi.org/10.1007/s12035-023-03668-2

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