期刊
STEM CELL REPORTS
卷 17, 期 10, 页码 2203-2219出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2022.08.010
关键词
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资金
- NYSCF
- ERC [602278, 771427]
- Swedish Research Council [2016-00873]
- Parkinsonfonden
- Hjarnfonden [FO2019-0301]
- Olle Engkvist Foundation [203-0006]
- Strategic Research Areas at Lund University MultiPark and StemTherapy
- Cure Parkinson's Trust in the UK
- Parkinson Canada [2018-00236]
- Canada Research Chair Program
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- Wellcome Trust [203151/Z/16/Z]
- FRQS
- Parkinson Quebec [268980]
- Canada Foundation for Innovation [38354]
- European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) [676408]
- Parkinson Canada
- European Research Council (ERC) [771427] Funding Source: European Research Council (ERC)
We have developed an efficient approach to generate functional induced dopaminergic neurons from adult human dermal fibroblasts and could specifically detect disease-relevant pathology in patient cells. These patient-derived neurons can serve as a cellular model to study age-related pathology relevant to Parkinson's disease.
We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibro-blasts. 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 neu-rons 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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