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Alzheimer's disease (AD) is characterized by tau pathology, leading to neurodegeneration. Astrocytes regulate central nervous system homeostasis and influence AD progression. The APOE3‐Christchurch (APOE3‐Ch) variant is linked to AD resilience, but its protective mechanisms remain unclear. Human induced pluripotent stem cell–derived astrocytes (APOE3‐Ch and wild type) were used to assess tau uptake, clearance, lipid metabolism, and transcriptomic adaptations. Fluorescently labeled 2N4R‐P301L tau oligomers were tracked, and pathway‐specific inhibitors dissected tau clearance mechanisms. Lipidomic and transcriptomic analyses were performed to identify genotype‐specific adaptations. APOE3‐Ch astrocytes exhibited enhanced tau uptake via heparan sulfate proteoglycan‐ and lipoprotein receptor‐related protein 1‐mediated pathways and superior clearance through lysosomal and proteasomal degradation. They exported less tau, limiting propagation. Transcriptomic analyses revealed upregulation of genes involved in cell projection assembly and endocytosis. Lipidomic profiling showed reduced ceramides and gamma‐linolenic acid, linked to decreased neuroinflammation and ferroptosis. APOE3‐Ch astrocytes promote tau clearance and metabolic adaptations, providing insights into genetic resilience in AD and potential therapeutic targets. APOE3‐Christchurch (APOE3‐Ch) astrocytes exhibit significantly increased tau internalization compared to wild‐type astrocytes, facilitated by upregulated heparan sulfate proteoglycan and low‐density lipoprotein receptor‐related protein 1 pathways. APOE3‐Ch astrocytes demonstrate more efficient tau degradation via both lysosomal and proteasomal pathways, while exporting significantly less tau, potentially reducing tau propagation in the central nervous system. APOE3‐Ch astrocytes show upregulation of genes involved in cell projection assembly and endocytosis, suggesting structural and functional modifications that enhance tau processing. Lipidomic profiling reveals reduced ceramide levels and gamma‐linolenic acid downregulation in APOE3‐Ch astrocytes, alterations linked to reduced neuroinflammatory and ferroptotic activity, contributing to the protective phenotype.

MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however, its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here, we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids, revealing a discrete developmental window (days 70–120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation, expressed SOX2, and lacked CRX, consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas, particularly through activation of MYC/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities, demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1, Flavopiridol) and the cell-cycle inhibitor Volasertib, indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively, our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma, establishes a robust and clinically relevant human retinal organoid platform, and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype.

Biomolecular condensates are found throughout a diversity of eukaryotic cell types and cellular compartments, playing roles in various cellular functions. A given protein generally forms functionally and compositionally heterogeneous condensates, but the underlying regulatory mechanisms are unknown. Here, we found that different RNA motifs modulate the formation of heterogeneous mRNA-protein condensates via riboregulation. Fragile X-related 1 (FXR1), an RNA-binding protein interacting with nuclear pores, assembles distinct localized subcellular mRNP condensates linked to cytosolic accumulation of G-quadruplex-containing pluripotent mRNAs and the localized translation of nucleoporin mRNAs at nuclear pores. The diverse locations of FXR1 condensates depend on the unique RNA-protein interaction modules of its two RNA binding domains, and the opposing effects of different RNA motifs on the affinity of FXR1 for nuclear pores. Notably, reduced FXR1 levels and impaired nuclear pore function lead to the nuclear accumulation of transcribed RNAs, facilitating fate transition in human embryonic stem cells. Preventing this decline would result in impaired hESC differentiation. Subject terms: RNA metabolism, Embryonic stem cells, RNA, RNA transport