HMGB1 Mediates Inflammation-Induced DMT1 Increase and Dopaminergic Neurodegeneration in the Early Stage of Parkinsonism
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
|---|---|
| Enthalten in: |
Molecular neurobiology - 61(2024), 4 vom: 28. Apr., Seite 2006-2020 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liang, Tuo [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 01.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s12035-023-03668-2 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36326423X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36326423X | ||
| 003 | DE-627 | ||
| 005 | 20240401232354.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s12035-023-03668-2 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1359.xml |
| 035 | |a (DE-627)NLM36326423X | ||
| 035 | |a (NLM)37833459 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liang, Tuo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a HMGB1 Mediates Inflammation-Induced DMT1 Increase and Dopaminergic Neurodegeneration in the Early Stage of Parkinsonism |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 28.03.2024 | ||
| 500 | |a Date Revised 01.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DMT1 | |
| 650 | 4 | |a Dopaminergic neurons | |
| 650 | 4 | |a HMGB1 | |
| 650 | 4 | |a Iron | |
| 650 | 4 | |a Neuroinflammation | |
| 650 | 4 | |a Parkinson’s disease | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Dopamine |2 NLM | |
| 650 | 7 | |a VTD58H1Z2X |2 NLM | |
| 650 | 7 | |a HMGB1 Protein |2 NLM | |
| 650 | 7 | |a Iron |2 NLM | |
| 650 | 7 | |a E1UOL152H7 |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Oxidopamine |2 NLM | |
| 650 | 7 | |a 8HW4YBZ748 |2 NLM | |
| 650 | 7 | |a solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 |2 NLM | |
| 650 | 7 | |a Hbp1 protein, rat |2 NLM | |
| 700 | 1 | |a Yang, Sheng-Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Li-Da |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Zhong-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Yung, Wing-Ho |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Ya |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular neurobiology |d 1990 |g 61(2024), 4 vom: 28. Apr., Seite 2006-2020 |w (DE-627)NLM012626961 |x 1559-1182 |7 nnns |
| 773 | 1 | 8 | |g volume:61 |g year:2024 |g number:4 |g day:28 |g month:04 |g pages:2006-2020 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s12035-023-03668-2 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 61 |j 2024 |e 4 |b 28 |c 04 |h 2006-2020 | ||