Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease
(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.
(Less)
- author
- organization
-
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Developmental and Regenerative Neurobiology (research group)
- Wallenberg Neuroscience Centre, Lund
- Molecular Neurogenetics (research group)
- Regenerative Neurophysiology (research group)
- publishing date
- 2022-09-09
- 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
- 2024-09-15 18:46:45
@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}}, }