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Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease

Brazdis, Razvan Marius ; Alecu, Julian E. ; Marsch, Daniel ; Dahms, Annika ; Simmnacher, Katrin ; Lörentz, Sandra LU ; Brendler, Anna ; Schneider, Yanni ; Marxreiter, Franz and Roybon, Laurent LU , et al. (2020) In Human Molecular Genetics 29(7). p.1180-1191
Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were... (More)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
29
issue
7
pages
12 pages
publisher
Oxford University Press
external identifiers
  • scopus:85084720812
  • pmid:32160287
ISSN
0964-6906
DOI
10.1093/hmg/ddaa039
language
English
LU publication?
yes
id
b6ada3ce-143e-4e97-ba36-61d9dcb723a6
date added to LUP
2020-06-09 09:18:48
date last changed
2024-04-17 09:27:31
@article{b6ada3ce-143e-4e97-ba36-61d9dcb723a6,
  abstract     = {{<p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.</p>}},
  author       = {{Brazdis, Razvan Marius and Alecu, Julian E. and Marsch, Daniel and Dahms, Annika and Simmnacher, Katrin and Lörentz, Sandra and Brendler, Anna and Schneider, Yanni and Marxreiter, Franz and Roybon, Laurent and Winner, Beate and Xiang, Wei and Prots, Iryna}},
  issn         = {{0964-6906}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{7}},
  pages        = {{1180--1191}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddaa039}},
  doi          = {{10.1093/hmg/ddaa039}},
  volume       = {{29}},
  year         = {{2020}},
}