Parkinson’s disease patient specific striatum organoids show hallmarks of increased inflammation#
Authors#
Kyriaki Barmpa, Claudia Saraiva, Alise Zagare, Mona Tuzza, Joseph Longworth, Elisa Zuccoli, Katrin Hufnagel, Florian Skwirblies, Ronny Schmidt, Dirk Brenner, Christoph Schröder and Jens C. Schwamborn
Abstract#
Background: Dopaminergic neurons from the substantia nigra pars compacta project their axons into the dorsal striatum, forming the nigrostriatal pathway. In Parkinson’s disease (PD), dopaminergic terminals degenerate in the striatum, leading to dopamine depletion, which in turn causes alterations in the basal ganglia circuits that are essential for movement control. However, the reasons of dopaminergic neuron terminals degeneration in the striatum are still not understood. The LRRK2 gene is highly expressed in the striatum and the LRRK2-G2019S mutation is one of the most common mutations associated with Parkinson’s disease. It is therefore tempting to speculate that dysregulations in the striatal functionality can initiate or contribute to the dopaminergic neuron terminals’ degeneration.
Objectives: We aimed to examine the phenotypic differences between healthy and patient striatum organoids carrying the LRRK2-G2019S mutation, to assess whether specific alterations in the striatum that are independent of dopaminergic input, could contribute to the development of the disease.
Methods: Striatum organoids were generated using healthy and PD patient induced pluripotent stem cell lines, and they were cultured until day 80. We evaluated the levels of striatum specific proteins, and we performed proteomics and kinase activity analysis.
Results: Parkinson’s disease striatum organoids revealed increased abundance of DRD2, DARPP32 and CDK5. Proteomics and kinase activity analysis demonstrated an inflammatory phenotype, which was further validated by investigating the occurrence of reactive astrocytes.
Conclusions: Striatum organoids recapitulate PD relevant phenotypes autonomously, independent of dopaminergic input. This includes a significant inflammatory phenotype.
