Upregulated ECM genes and increased synaptic activity in Parkinson's human DA neurons with PINK1/ PRKN mutations.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
18 May 2024
18 May 2024
Historique:
received:
08
01
2023
accepted:
25
04
2024
medline:
19
5
2024
pubmed:
19
5
2024
entrez:
18
5
2024
Statut:
epublish
Résumé
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but PD also affects the hippocampus and cortex, usually in its later stage. Approximately 15% of PD cases are familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PRKN. In vitro studies of these genetic mutations are needed to understand the neurophysiological changes in patients' neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from human induced pluripotent stem cells (hiPSCs) derived from two patients with a double mutation in their PINK1 and PRKN (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PRKN mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top two upregulated pathways in the mutant PD neurons. Our findings reveal that the phenotypes linked to PINK1 and PRKN mutations differ from those from other PD mutations, suggesting a unique interplay between these two mutations that drives different PD mechanisms.
Identifiants
pubmed: 38762512
doi: 10.1038/s41531-024-00715-0
pii: 10.1038/s41531-024-00715-0
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103Subventions
Organisme : Israel Science Foundation (ISF)
ID : 1994/21
Organisme : Israel Science Foundation (ISF)
ID : 3252/21
Informations de copyright
© 2024. The Author(s).
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