TY - JOUR T1 - Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson’s disease JF - bioRxiv DO - 10.1101/2021.04.23.441070 SP - 2021.04.23.441070 AU - Janelle Drouin-Ouellet AU - Karolina Pircs AU - Emilie M. Legault AU - Marcella Birtele AU - Fredrik Nilsson AU - Shelby Shrigley AU - Maria Pereira AU - Petter Storm AU - Yogita Sharma AU - Romina Vuono AU - Thomas B. Stoker AU - Johan Jakobsson AU - Roger A. Barker AU - Malin Parmar Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/23/2021.04.23.441070.abstract N2 - Understanding the pathophysiology of Parkinson’s disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinson’s disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinson’s disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinson’s disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinson’s disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinson’s disease.Abbreviationsαsynalpha-synucleinALDH1A1aldehyde dehydrogenase 1 family member A1ACSFartificial cerebrospinal fluidCMAchaperone-mediated autophagyDAPI4’,6-diamidino-2-phenylindoleDMSOdimethyl sulfoxideGSEAgene set enrichment analysisENMearly neural differentiation mediumDAdopaminergicHSC70Heat shock cognate 71 kDa proteiniDANsinduced DA neuronsiNsinduced neuronsiPSCsinduced pluripotent stem cellsLAMP2lysosome-associated membrane protein 2LC3microtubule-associated protein 1 light chain 3 betaLNMLate neuronal mediumPGKphosphoglycerate kinaseRESTRE1-silencing Transcription FactorTTXtetrodotoxinTHtyrosine hydroxylaseVIMvimentinWBwestern blot ER -