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Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease

Drouin-Ouellet, Janelle LU ; Legault, Emilie M ; Nilsson, Fredrik LU orcid ; Pircs, Karolina LU orcid ; Bouquety, Julie ; Petit, Florence ; Shrigley, Shelby LU orcid ; Birtele, Marcella LU orcid ; Pereira, Maria LU and Storm, Petter LU orcid , et al. (2022) In Stem Cell Reports 17(10). p.2203-2219
Abstract

We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of... (More)

We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Stem Cell Reports
volume
17
issue
10
pages
2203 - 2219
publisher
Cell Press
external identifiers
  • pmid:36150382
  • scopus:85139348119
ISSN
2213-6711
DOI
10.1016/j.stemcr.2022.08.010
language
English
LU publication?
yes
additional info
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
id
40fe8f96-0b25-4de5-8504-52bf18be55c4
date added to LUP
2022-10-14 10:58:02
date last changed
2024-06-23 10:26:00
@article{40fe8f96-0b25-4de5-8504-52bf18be55c4,
  abstract     = {{<p>We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.</p>}},
  author       = {{Drouin-Ouellet, Janelle and Legault, Emilie M and Nilsson, Fredrik and Pircs, Karolina and Bouquety, Julie and Petit, Florence and Shrigley, Shelby and Birtele, Marcella and Pereira, Maria and Storm, Petter and Sharma, Yogita and Bruzelius, Andreas and Vuono, Romina and Kele, Malin and Stoker, Thomas B and Ottosson, Daniella Rylander and Falk, Anna and Jakobsson, Johan and Barker, Roger A and Parmar, Malin}},
  issn         = {{2213-6711}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{10}},
  pages        = {{2203--2219}},
  publisher    = {{Cell Press}},
  series       = {{Stem Cell Reports}},
  title        = {{Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease}},
  url          = {{http://dx.doi.org/10.1016/j.stemcr.2022.08.010}},
  doi          = {{10.1016/j.stemcr.2022.08.010}},
  volume       = {{17}},
  year         = {{2022}},
}