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

Janelle Drouin-Ouellet, Emilie M Legault, Fredrik Nilsson, Karolina Pircs, Julie Bouquety, Florence Petit, Shelby Shrigley, Marcella Birtele, Maria Pereira, Petter Storm, Yogita Sharma, Andreas Bruzelius, Romina Vuono, Malin Kele, Thomas B Stoker, Daniella Rylander Ottosson, Anna Falk, Johan Jakobsson, Roger A Barker, Malin Parmar

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2203-2219
JournalStem Cell Reports
Volume17
Issue number10
Early online date2022 Sep 9
DOIs
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Neurosciences
  • Neurology

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