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Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease.
Drouin-Ouellet, Janelle; Legault, Emilie M; Nilsson, Fredrik; Pircs, Karolina; Bouquety, Julie; Petit, Florence; Shrigley, Shelby; Birtele, Marcella; Pereira, Maria; Storm, Petter; Sharma, Yogita; Bruzelius, Andreas; Vuono, Romina; Kele, Malin; Stoker, Thomas B; Ottosson, Daniella Rylander; Falk, Anna; Jakobsson, Johan; Barker, Roger A; Parmar, Malin.
Afiliação
  • Drouin-Ouellet J; Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada. Electronic address: janelle.drouin-ouellet@umontreal.ca.
  • Legault EM; Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • Nilsson F; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Pircs K; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Bouquety J; Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • Petit F; Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • Shrigley S; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Birtele M; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Pereira M; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Storm P; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Sharma Y; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Bruzelius A; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Vuono R; Wellcome-MRC Cambridge Stem Cell Institute & John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK; Medway School of Pharmacy, University of Kent, Chatham Maritime, Chatham ME4 4TB, UK.
  • Kele M; Department of Neuroscience, Karolinska institutet, Stockholm, Sweden.
  • Stoker TB; Wellcome-MRC Cambridge Stem Cell Institute & John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK.
  • Ottosson DR; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Falk A; Department of Neuroscience, Karolinska institutet, Stockholm, Sweden.
  • Jakobsson J; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden.
  • Barker RA; Wellcome-MRC Cambridge Stem Cell Institute & John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK.
  • Parmar M; Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11 and B10, S-221 84 Lund, Sweden. Electronic address: malin.parmar@med.lu.se.
Stem Cell Reports ; 17(10): 2203-2219, 2022 10 11.
Article em En | MEDLINE | ID: mdl-36150382
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Células-Tronco Pluripotentes Induzidas Limite: Adult / Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Células-Tronco Pluripotentes Induzidas Limite: Adult / Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2022 Tipo de documento: Article