Ferroptosis-related factors in the substantia nigra are associated with Parkinson's disease.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 09 2023
16 09 2023
Historique:
received:
11
07
2023
accepted:
12
09
2023
medline:
18
9
2023
pubmed:
17
9
2023
entrez:
16
9
2023
Statut:
epublish
Résumé
Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein-protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell-cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons' DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons' sensitivity to ferroptosis.
Identifiants
pubmed: 37717088
doi: 10.1038/s41598-023-42574-4
pii: 10.1038/s41598-023-42574-4
pmc: PMC10505210
doi:
Substances chimiques
Ceruloplasmin
EC 1.16.3.1
Iron
E1UOL152H7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15365Informations de copyright
© 2023. Springer Nature Limited.
Références
JAMA. 2014 Apr 23-30;311(16):1670-83
pubmed: 24756517
Free Radic Res. 2001 Aug;35(2):111-8
pubmed: 11697191
Front Aging Neurosci. 2019 Dec 19;11:351
pubmed: 31920630
Ann Neurol. 2013 Apr;73(4):554-9
pubmed: 23424051
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Exp Mol Med. 2022 Feb;54(2):91-102
pubmed: 35217834
J Parkinsons Dis. 2018;8(s1):S3-S8
pubmed: 30584159
Am J Cancer Res. 2019 Apr 01;9(4):730-739
pubmed: 31105999
Neurology. 2004 Nov 23;63(10):1912-7
pubmed: 15557511
Mov Disord. 2011 May;26(6):1015-21
pubmed: 21626546
J Clin Invest. 1996 Jul 1;98(1):207-15
pubmed: 8690795
Free Radic Biol Med. 2020 Dec;161:60-70
pubmed: 33017631
Neuroscience. 2015 Jan 22;284:234-246
pubmed: 25301748
Blood. 2006 Jan 1;107(1):328-33
pubmed: 16141345
Parkinsonism Relat Disord. 2009 Jan;15 Suppl 1:S3-8
pubmed: 19131039
Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2539-43
pubmed: 7708681
Signal Transduct Target Ther. 2016 Sep 02;1:16015
pubmed: 29263898
Am J Clin Nutr. 2017 Dec;106(Suppl 6):1559S-1566S
pubmed: 29070551
J Clin Invest. 2023 May 15;133(10):
pubmed: 37183824
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Lancet. 2021 Apr 24;397(10284):1577-1590
pubmed: 33667416
Lancet. 2021 Jun 12;397(10291):2284-2303
pubmed: 33848468
Ther Adv Neurol Disord. 2009 Jan;2(1):51-60
pubmed: 21180641
Brain Behav. 2018 Jun;8(6):e00995
pubmed: 29733522
Nat Rev Mol Cell Biol. 2021 Apr;22(4):266-282
pubmed: 33495651
Brain Res. 1996 Nov 4;738(2):265-74
pubmed: 8955522
Mol Med. 2014 Mar 24;20:138-46
pubmed: 24531836
Exp Neurol. 2016 Jan;275 Pt 1:220-31
pubmed: 26555088
Cell Death Dis. 2022 Nov 28;13(11):1006
pubmed: 36443285
J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):368-76
pubmed: 18344392
Cell Metab. 2008 Sep;8(3):182-3
pubmed: 18762018
Nat Neurosci. 2022 May;25(5):588-595
pubmed: 35513515
Nat Neurosci. 2019 Jul;22(7):1099-1109
pubmed: 31235907
Nat Rev Genet. 2021 Feb;22(2):71-88
pubmed: 33168968
Prog Neurobiol. 2021 Jan;196:101890
pubmed: 32726602
ASN Neuro. 2020 Jan-Dec;12:1759091420962681
pubmed: 32993319
Physiol Rev. 1987 Apr;67(2):520-82
pubmed: 3550839
Nature. 2019 Nov;575(7784):688-692
pubmed: 31634900
Nat Rev Neurosci. 2017 Mar 17;18(4):251-259
pubmed: 28303016
J Parkinsons Dis. 2019;9(3):501-515
pubmed: 31282427
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Front Neurosci. 2019 Dec 11;13:1195
pubmed: 31920471
J Biol Chem. 1997 Aug 8;272(32):20185-90
pubmed: 9242695
Nucleic Acids Res. 2023 Jan 6;51(D1):D571-D582
pubmed: 36305834