GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313031/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313031GEOGSEfalseLRRK2-G2019S Impairs Astrocyte Differentiation and Triggers a senescence-like phenotype in Parkinson's Disease Models - Midbrain organoidsAstrocytes are increasingly recognised as essential contributors to both physiological brain function and neurodegenerative diseases. 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. Notably, pharmacological activation of the developmental transcription factor NR2F1, downregulated in LRRK2-G2019S models, reduced astrocyte cell death and senescence-like phenotypes. Together, these data show that LRRK2-G2019S impairs astrocyte specification and predisposes to a senescent phenotype.2026/05/19GSE313031GSM9359395GSM9359384GSM9359396GSM9359385GSM9359386GSM9359397GSM9359398GSM9359387GSM9359388GSM9359399GSM9359389GSM9359400GSM9359390GSM9359391GSM9359392GSM9359393GSM9359383GSM935939424676313031Homo sapiens