🎙️ Episode 58: Aneuploid Cells and Cellular Battles — How Cell Interactions Shape Genome Integrity

🧬 In this episode of Base by Base, we explore a groundbreaking study by Fusari et al. (2025), published in Cell Genomics, that reveals how the fate of aneuploid cells is influenced not only by their own genetic imbalances but also by their neighbors. Using Drosophila models, the authors dissect the role of cell-to-cell interactions in eliminating cells with chromosomal losses or gains, uncovering a nuanced landscape of cellular competition driven by gene dosage sensitivity.

🔍 Study highlights:
Segmental monosomies as small as a few hundred genes can impair clonal growth and trigger competitive elimination, even in regions without known haploinsufficient genes.
Segmental trisomies of up to 1,500 genes generally do not impair growth — and in some contexts, actually promote overgrowth when juxtaposed with monosomic cells.
The effects of aneuploidy are not solely cell-autonomous: when monosomic and trisomic clones share the same genomic region, their interactions can enhance or suppress deleterious outcomes.
Different types of cell competition emerge depending on the gene content of the aneuploid region — including “lethal competition” (e.g., involving RpL26) and “super-competition” (e.g., involving flower, Diap1, Notum).
Trisomic clones can either exacerbate monosomy-induced cell death or, paradoxically, support the growth of nearby underperforming cells via compensatory mechanisms.

🧠 Conclusion:
This study challenges the classical view of aneuploidy as uniformly deleterious. By revealing how genomic content and cellular context shape the behavior of chromosomally unbalanced cells, Fusari et al. provide a powerful model for understanding how mosaicism is resolved in development — and potentially targeted in disease. The findings pave the way for new strategies in cancer biology, regenerative medicine, and developmental genetics.

📖 Reference:
Fusari, E., Muzzopappa, M., Gracia, J., & Milán, M. (2025). Depletion of aneuploid cells is shaped by cell-to-cell interactions. Cell Genomics, 5, 100894. https://doi.org/10.1016/j.xgen.2025.100894

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0

🎙️ Episode 57: Low Uptake of Genetic Testing in Medicaid-Enrolled Children with ASD and Intellectual Disability

🧬 In this episode of Base by Base, we delve into a comprehensive analysis by Brown et al. (2025) published in Genetics in Medicine, which examined Medicaid and CHIP claims from 2008 to 2016 for over 241,000 children aged 7 to 17. The study aimed to assess how well professional guidelines recommending genetic testing for autism spectrum disorder (ASD) and intellectual disability (ID) have been implemented in a racially and socioeconomically diverse, publicly insured population .

🔍 Key findings: The authors found that only a quarter of children diagnosed with both ASD and ID received any genetic testing, while 16.9% of those with ASD only and 13.1% of those with ID only underwent testing, compared with just 1.2% in a randomly sampled control group. Testing modalities remained outdated for years, with cytogenetics and Fragile X assays dominating until 2013, before chromosomal microarray and gene panel use began to rise. Significant disparities surfaced: non-Hispanic Black children were less likely, and Hispanic children more likely, to receive testing than non-Hispanic White peers, and those living in suburban or rural areas had lower testing rates compared to urban residents. Moreover, fewer than 6% of first tests occurred at ages 15–17, highlighting missed diagnostic opportunities in adolescence .

🧠 Conclusion: The persistently low frequency of guideline-recommended genetic testing and the lag in adopting advanced modalities underscore critical implementation gaps in Medicaid settings. Tackling socioeconomic, racial, and geographic barriers is essential to enhance diagnostic yield, inform precision medicine approaches, and ultimately improve care for underserved children with neurodevelopmental disorders .

📖 Reference:
Brown, T. R., Lee, W.-L., Ventimiglia, J., Thurm, A., Levy, T., Yuan, V., Martinez-Agosto, J. A., & Shea, L. L. (2025). Medicaid claims from 2008 to 2016 indicate low rates of genetic testing among children with intellectual disability and autism spectrum disorder. Genetics in Medicine. https://doi.org/10.1016/j.gim.2025.101451

📜 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 56: Neuronal Immunoproteasome — A Metabolic Trigger for Ferroptotic Neurodegeneration in Multiple Sclerosis

🧬 In this episode of Base by Base, we examine the transformative findings of Woo et al. (2025) in Cell, revealing how inflammation reshapes neuronal proteostasis. Under interferon-γ–driven stress, neurons incorporate the immunoproteasome subunit PSMB8 into their core proteasome, profoundly impairing catalytic function. This shift undermines the degradation of the glycolytic regulator PFKFB3, setting off a cascade of metabolic reprogramming that favors glycolysis over the pentose phosphate pathway, depletes antioxidant defenses, and precipitates oxidative injury.

🔍 Key highlights: the study demonstrates that interferon-γ–induced PSMB8 expression in neurons leads to a marked reduction in β5 catalytic activity, resulting in PFKFB3 accumulation and a metabolic switch that elevates reactive oxygen species and sensitizes cells to glutamate-induced excitotoxicity and ferroptosis. Neuron-specific genetic deletion of PSMB8 or systemic treatment with the immunoproteasome inhibitor ONX-0914 restores proteasome balance, prevents PFKFB3 buildup, replenishes glutathione pools, and confers robust neuroprotection in mouse models of multiple sclerosis. Parallel experiments targeting PFKFB3 with the small-molecule inhibitor Pfk-158 further validate the immunoproteasome–PFKFB3 axis as a therapeutic gateway.

🧠 Conclusion: this work positions the neuronal immunoproteasome as a critical nexus linking neuroinflammation to metabolic collapse and ferroptotic cell death, and proposes PSMB8 and PFKFB3 inhibition as promising strategies to safeguard neurons in multiple sclerosis and potentially other neurodegenerative disorders.

📖 Reference: Woo, M. S., Brand, J., Bal, L. C., Moritz, M., Walkenhorst, M., Vieira, V., Ipenberg, I., et al. (2025). The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis. Cell, 188, 1–19. https://doi.org/10.1016/j.cell.2025.05.029

📜 License: This episode is based on an open access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/