Parkinson's disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties
Azevedo, Carla LU ; Teku, Gabriel LU ; Pomeshchik, Yuriy LU
; Reyes, Juan F
LU
; Chumarina, Margarita
LU
; Russ, Kaspar
LU
; Savchenko, Ekaterina
LU
; Hammarberg, Anna
LU
; Lamas, Nuno Jorge
LU
and Collin, Anna
LU
, et al.
(2022)
In Proceedings of the National Academy of Sciences of the United States of America
119(12).
- Abstract
Significance Our results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.
Abstract Limited evidence has shed light on how aSYN proteins affect the
oligodendrocyte phenotype and pathogenesis in synucleinopathies that
include Parkinson’s disease (PD) and multiple system atrophy (MSA).... (More)Significance Our results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.
Abstract Limited evidence has shed light on how aSYN proteins affect the
(Less)
oligodendrocyte phenotype and pathogenesis in synucleinopathies that
include Parkinson’s disease (PD) and multiple system atrophy (MSA).
Here, we investigated early transcriptomic changes within PD and MSA O4+
oligodendrocyte lineage cells (OLCs) generated from patient-induced
pluripotent stem cells (iPSCs). We found impaired maturation of PD and
MSA O4+ OLCs compared to controls. This phenotype was
associated with changes in the human leukocyte antigen (HLA) genes, the
immunoproteasome subunit PSMB9, and the complement component C4b for
aSYN p.A53T and MSA O4+ OLCs, but not in SNCAtrip O4+ OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4+
OLCs, whereas exogenous treatment with aSYN species led to significant
toxicity. Notably, transcriptome profiling of genes encoding proteins
forming Lewy bodies and glial cytoplasmic inclusions revealed clustering
of PD aSYN p.A53T O4+ OLCs with MSA O4+ OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4+ OLCs.
- author
- Azevedo, Carla
LU
; Teku, Gabriel
LU
; Pomeshchik, Yuriy
LU
; Reyes, Juan F
LU
; Chumarina, Margarita
LU
; Russ, Kaspar
LU
; Savchenko, Ekaterina
LU
; Hammarberg, Anna
LU
; Lamas, Nuno Jorge
LU
and Collin, Anna
LU
, et al. (More)
- Azevedo, Carla
LU
; Teku, Gabriel
LU
; Pomeshchik, Yuriy
LU
; Reyes, Juan F
LU
; Chumarina, Margarita
LU
; Russ, Kaspar
LU
; Savchenko, Ekaterina
LU
; Hammarberg, Anna
LU
; Lamas, Nuno Jorge
LU
; Collin, Anna
LU
; Gouras, Gunnar K
LU
; Klementieva, Oxana
LU
; Hallbeck, Martin
; Taipa, Ricardo
; Vihinen, Mauno
LU
and Roybon, Laurent
LU
(Less)
- organization
-
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- IPSC Laboratory for CNS Disease Modeling (research group)
- The genetics of soft tissue tumors (research group)
- Division of Clinical Genetics
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Neural stem cells (research group)
- Molecular Neurogenetics (research group)
- Experimental Dementia Research (research group)
- LINXS - Institute of advanced Neutron and X-ray Science
- NanoLund: Centre for Nanoscience
- Medical Microspectroscopy (research group)
- Protein Bioinformatics (research group)
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 119
- issue
- 12
- article number
- e2111405119
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85126726468
- pmid:35294277
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.2111405119
- language
- English
- LU publication?
- yes
- id
- 37db1437-e858-44e2-bfb7-e121ccac07d3
- date added to LUP
- 2022-03-27 11:18:53
- date last changed
- 2024-06-13 13:51:08
@article{37db1437-e858-44e2-bfb7-e121ccac07d3,
abstract = {{<p>Significance Our results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.</p><p>Abstract Limited evidence has shed light on how aSYN proteins affect the <br>
oligodendrocyte phenotype and pathogenesis in synucleinopathies that <br>
include Parkinson’s disease (PD) and multiple system atrophy (MSA). <br>
Here, we investigated early transcriptomic changes within PD and MSA O4<sup>+</sup><br>
oligodendrocyte lineage cells (OLCs) generated from patient-induced <br>
pluripotent stem cells (iPSCs). We found impaired maturation of PD and <br>
MSA O4<sup>+</sup> OLCs compared to controls. This phenotype was <br>
associated with changes in the human leukocyte antigen (HLA) genes, the <br>
immunoproteasome subunit PSMB9, and the complement component C4b for <br>
aSYN p.A53T and MSA O4<sup>+</sup> OLCs, but not in <i>SNCA</i><sup>trip</sup> O4<sup>+</sup> OLCs despite high levels of aSYN assembly formation. Moreover, <i>SNCA</i> overexpression resulted in the development of O4<sup>+</sup><br>
OLCs, whereas exogenous treatment with aSYN species led to significant <br>
toxicity. Notably, transcriptome profiling of genes encoding proteins <br>
forming Lewy bodies and glial cytoplasmic inclusions revealed clustering<br>
of PD aSYN p.A53T O4<sup>+</sup> OLCs with MSA O4<sup>+</sup> OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4<sup>+</sup> OLCs.</p>}},
author = {{Azevedo, Carla and Teku, Gabriel and Pomeshchik, Yuriy and Reyes, Juan F and Chumarina, Margarita and Russ, Kaspar and Savchenko, Ekaterina and Hammarberg, Anna and Lamas, Nuno Jorge and Collin, Anna and Gouras, Gunnar K and Klementieva, Oxana and Hallbeck, Martin and Taipa, Ricardo and Vihinen, Mauno and Roybon, Laurent}},
issn = {{1091-6490}},
language = {{eng}},
number = {{12}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Parkinson's disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties}},
url = {{http://dx.doi.org/10.1073/pnas.2111405119}},
doi = {{10.1073/pnas.2111405119}},
volume = {{119}},
year = {{2022}},
}