LRRK2-G2019S Impairs Astrocyte Differentiation and Triggers a senescence-like phenotype in Parkinson's Disease Models - Brain samples

Here, we describe how the Parkinson’s disease (PD)-associated mutation LRRK2-G2019S affects astrocytes using autoptic brain samples and PD patient-specific 3D midbrain organoids and 2D astrocytes derived from induced pluripotent stem cells. In autoptic midbrain samples from LRRK2-G2019S patients, we observed a reduction in GFAP⁺ astrocytes but increased branching, together with transcriptional signatures consistent with altered astrocyte function.

We also observed delayed astrocyte differentiation in PD patient-specific midbrain organoids, accompanied by altered astrocyte transcriptomic profiles revealed by single-cell RNA sequencing. This defective differentiation contributes to the acquisition of a senescent-like phenotype. In 2D cultures, astrocyte differentiation from LRRK2-G2019S precursor cells was associated with early apoptosis and altered Wnt/β-catenin and TGFβ signalling compared to LRRK2-WT cultures.