Drouin-Ouellet, Janelle, Legault, Emilie M, Nilsson, Fredrik, Pircs, Karolina, Bouquety, Julie, Petit, Florence, Shrigley, Shelby, Birtele, Marcella, Pereira, Maria, Storm, Petter, and others. (2022) Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease. Stem cell reports, 17 (10). pp. 2203-2219. ISSN 2213-6711. (doi:10.1016/j.stemcr.2022.08.010) (KAR id:97572)
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Language: English 
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| Official URL: https://doi.org/10.1016/j.stemcr.2022.08.010 |
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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 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.
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1016/j.stemcr.2022.08.010 |
| Uncontrolled keywords: | Dopaminergic neurons, Autophagy, Parkinson's Disease, alpha-Synuclein, Induced Pluripotent Stem Cells, Induced Neurons, Direct Neural Reprogramming, Humans, Parkinson Disease, Adult, Dopaminergic Neurons |
| Subjects: |
R Medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Divisions > Division of Natural Sciences > Medway School of Pharmacy |
| Funders: |
European Research Council (https://ror.org/0472cxd90)
Swedish Research Council (https://ror.org/03zttf063) National Institute for Health Research (https://ror.org/0187kwz08) Wellcome Trust (https://ror.org/029chgv08) |
| SWORD Depositor: | JISC Publications Router |
| Depositing User: | JISC Publications Router |
| Date Deposited: | 14 Aug 2024 13:45 UTC |
| Last Modified: | 14 Aug 2024 23:54 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/97572 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Vuono, Romina.
| Creator's ORCID: |
 https://orcid.org/0000-0002-5162-3422
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