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

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...

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Published in:Molecular neurobiology 2024-04, Vol.61 (4), p.2006-2020
Main Authors: Liang, Tuo, Yang, Sheng-Xi, Qian, Christopher, Du, Li-Da, Qian, Zhong-Ming, Yung, Wing-Ho, Ke, Ya
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
Animals
Basal ganglia
Biomedical and Life Sciences
Biomedicine
Cell Biology
Central nervous system diseases
Cytokines
Cytokines - metabolism
Divalent metal transporter-1
Dopamine - metabolism
Dopamine receptors
Dopaminergic Neurons - metabolism
High mobility group proteins
HMGB1 protein
HMGB1 Protein - metabolism
Inflammation
Inflammation - pathology
Iron
Iron - metabolism
Lipopolysaccharides
Movement disorders
Neurobiology
Neurodegeneration
Neurodegenerative diseases
Neurology
Neuronal-glial interactions
Neurons
Neurosciences
Oxidopamine
Parkinson Disease - pathology
Parkinson's disease
Parkinsonian Disorders - metabolism
Rats
Regulatory sequences
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Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-023-03668-2