02758nas a2200313   4500000000100000000000100001008004100002653001700043653002400060653001700084653002300101100001900124700002000143700001700163700001500180700002100195700001800216700002000234700002300254700001800277700001700295700002400312700002300336245010100359856006200460490000800522520190000530022001402430                                       d10aLRRK2-G2019S10aParkinson's disease10aInflammation10astriatum organoids1 aKyriaki Barmpa1 aClaudia Saraiva1 aAlise Zagare1 aMona Tuzza1 aJoseph Longworth1 aElisa Zuccoli1 aKatrin Hufnagel1 aFlorian Skwirblies1 aRonny Schmidt1 aDirk Brenner1 aChristoph Schröder1 aJens C. Schwamborn00aParkinson's Disease Patient-Specific Striatum Organoids Show Hallmarks of Increased Inflammation  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/mds.701760 vn/a3 aBackground 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 for dopaminergic neuron terminal 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 PD. 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 PD 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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.  a1531-8257