Highlights d CUL2 FEM1B recognizes reduced FNIP1 through two interface zinc ions d Zn 2+ is essential for reductive stress signaling d FNIP1 access to CUL2 FEM1B is gated by BEX protein pseudosubstrate inhibitors d Mutation of FEM1B and BEX deletion cause similar developmental syndromes

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Human disease commonly manifests as a result of complex genetic and environmental interactions. In the case of neurodegenerative diseases, such as Parkinson's disease (PD), understanding how environmental exposures collude with genetic polymorphisms in the central nervous system (CNS) to cause dysfunction is critical in order to develop better treatment strategies, therapies, and a more cohesive paradigm for future research. The intersection of genetics and the environment in disease etiology is particularly relevant in the context of their shared pathophysiological mechanisms. This review offers an integrated view of disease-toxicant interactions in PD. Particular attention is dedicated to how mutations in the genes SNCA, parkin, leucine-rich repeat kinase 2 (LRRK2) and DJ-1, as well as dysfunction of the ubiquitin proteasome system, may contribute to PD and how exposure to heavy metals, pesticides and illicit drugs may further the consequences of these mutations to exacerbate PD and PD-like disorders. Although the toxic effects induced by exposure to these environmental factors may not be the primary causes of PD, their mechanisms of action are critical for our current understanding of the neuropathologies driving PD. Elucidating how environment and genetics collude to cause pathogenesis of PD will facilitate the development of more effective treatments for the disease. Additionally, we discuss the neuroprotection exerted by estrogen and other compounds that may prevent PD and provide an overview of current treatment strategies and therapies.

The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1.

Sex disparity in both cancer incidence and response to therapeutics, especially immunotherapy, has become an important area of research in recent years. Brain tumors show obvious sex biases in incidence and therapy response. Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and similar to other brain tumors, males have consistently higher incidence across all subgroups and at all ages. Moreover, for patients >3 years of age, females have significantly better outcomes than males. However, molecular drivers of such sex disparity in incidence and prognosis remain unclear.Here, we report a male-biased function of an oncogene, YAP1, in MB formation and immune suppression. Integrated multi-platform genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses show that YAP1 promotes cancer stem cell maintenance through concurrent transcriptional activation of stemness genes, such as Sox2, and repression of differentiation regulators such as NeuroD1 and Zic1/2. YAP1 expression in MB cells also inhibits anti-tumor immune cell infiltration by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGFb, and CCL5 Pathways. Notably, we found that YAP1 genetic deletion results in disproportionately higher survival of males than females in a spontaneous mouse model of infantile SHH MB, despite equivocal expression levels in both sexes. Consistent with our findings in mouse models, YAP1 downstream genes stratify MB patient survival in males but not females. Finally, we show that a brain-penetrant YAP1 inhibitor, verteporfin, extends survival and enhances immune infiltrates in vivo, mimicking the effects of Yap1 genetic deletion. In summary, this study demonstrates that an oncogene function may be sex-biased and underscores the need to incorporate sex as a variable in cancer mechanisms, tumor immunology, and treatment response studies. Citation Format: Nourhan Abdelfattah, Sivaraman Natarajan, Jose Maldonado, Han Nhat Tran, Hannah Borland, Rachael McMinimy, Shu-Hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun. Sex-biased function of an oncogene, YAP1, regulates medulloblastoma stem cells and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1708.