TY - JOUR T1 - Synaptic decline precedes dopaminergic neuronal loss in human midbrain organoids harboring a triplication of the <em>SNCA</em> gene JF - bioRxiv DO - 10.1101/2021.07.15.452499 SP - 2021.07.15.452499 AU - Jennifer Modamio AU - Claudia Saraiva AU - Gemma Gomez Giro AU - Sarah Louise Nickels AU - Javier Jarazo AU - Paul Antony AU - Peter Barbuti AU - Rashi Hadler AU - Christian Jäger AU - Rejko Krüger AU - Enrico Glaab AU - Jens Christian Schwamborn Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/15/2021.07.15.452499.abstract N2 - Increased levels of the protein alpha-synuclein (α-syn) are associated with the development of neurodegenerative diseases like Parkinson’s disease (PD). In physiological conditions, α-syn modulates synaptic plasticity, neurogenesis and neuronal survival. However, its pathogenic accumulation and aggregation results in toxicity and neurodegeneration.Here, we used a PD patient specific midbrain organoid model derived from induced pluripotent stem cells harboring a triplication in the SNCA gene to study PD-associated phenotypes. The model recapitulates the two main hallmarks of PD, which are α-syn aggregation and loss of dopaminergic neurons. Additionally, impairments in astrocyte differentiation were detected. Transcriptomics data indicate that synaptic function is impaired in PD specific midbrain organoids. This is further confirmed by alterations in synapse number and electrophysiological activity. We found that synaptic decline precedes neurodegeneration. Finally, this study substantiates that patient specific midbrain organoids allow a personalized phenotyping, which make them an interesting tool for precision medicine and drug discovery.Competing Interest StatementJCS and JJ are co-founders and shareholders of the biotech company OrganoTherapeutics SARL. ER -