Neurodegeneration is increasingly recognized not only as a disorder of neurons but also as a breakdown of dialogue between the nervous and immune systems. Recent discoveries reveal that immune cells and inflammatory signals are deeply interwoven with brain function across the lifespan. Far from passive responders, immune cells act as sentinels and shapers of neuronal resilience, vulnerability, and repair. Together, robust data support a model in which neurodegeneration emerges from complex interactions between neural and immune networks, positioning the immune system as both a sensor and driver of brain health. This perspective synthesizes a growing body of work arguing that neurodegenerative diseases are a failure of neuroimmune crosstalk-where protective signals are lost, and maladaptive responses take hold. By restoring immune homeostasis, fine-tuning inflammatory responses, or targeting epigenetic regulators of the immune state, it may be possible not only to slow degeneration but also to promote recovery. We outline the key challenges and opportunities for this paradigm shift and highlight how a deeper integration of neuroscience and immunology could transform the future of treating neurodegenerative diseases. Lastly, we describe critical focus areas to improve our understanding of neurodegeneration and highlight the development of immune-based therapeutics for neurodegeneration.
F. C. Bennett, Soyon Hong, Ning Jiang et al.· Cell· 0 citations
Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary-heart signaling circuits modulate cardiac function with aging. We further identify ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin and glucose levels, as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.
Christy M. Nguyen, L. Velez, Youngseo Cheon et al.· Journal of Clinical Investig...· 0 citations