2026-09-24T22:28:29Zhttps://api.repository.cam.ac.uk/server/oai/request

oai:www.repository.cam.ac.uk:1810/3899312026-08-25T00:41:38Zcom_1810_221925com_1810_34581col_1810_224160

Cytosolic Nucleic Acid Sensing and Senescence in a Patient-Derived Model of Progressive Multiple Sclerosis https://doi.org/10.17863/CAM.121667 Prasad, Pranathi Pluchino, Stefano Multiple Sclerosis (MS) is an inflammatory, autoimmune disorder of the central nervous system (CNS) affecting 2.8 million people worldwide and characterised by an attack by adaptive immune cells against myelin. For reasons not yet fully understood, most patients eventually transition to a disease stage known as progressive MS (P-MS), involving a shift from adaptive immune disease mechanisms to a CNS-compartmentalised innate immune response. During P-MS, the inflammatory activity of CNS-resident cells is thought to drive axonal degeneration, neuronal loss and the irreversible accumulation of disability. The treatment options for P-MS are currently extremely limited. Ageing and senescence are implicated as critical drivers of disease progression, and cellular senescence has been observed in immature cells resembling neural stem cells within brain lesions of patients with P-MS. Prior research demonstrates that directly induced neural stem cells (iNSCs) derived from patients with P-MS exhibit an inherent senescent phenotype and intrinsic dysfunctions including heightened inflammation and altered metabolism. However, the precise mechanisms driving cellular senescence and their contributions to the pathobiological processes in P-MS remain poorly understood. Using patient-derived iNSCs as a model for P-MS, my PhD aimed to uncover the mechanisms underpinning senescence and to study its role in driving pathological changes in the P-MS brain. In this thesis, I conducted phosphoproteomic analysis and identified key dysregulations in pathways related to senescence and antiviral responses in patient-derived cells. Using biochemical assays, I unveiled the accumulation of mitochondria-derived double-stranded RNA (mt-dsRNA) in the cytosol of P-MS iNSCs, driving activation of the antiviral RIG-I/MDA5-MAVS signalling pathway. I found this accumulation of mt-dsRNA to be a key driver of senescence, innate immune activation through the TBK1-IRF3 axis, and the secretion of paracrine inflammatory factors capable of transferring a reactive, interferon-responsive and disease-associated phenotype to astrocytes. Notably, interventions inhibiting the sensing of this mt-dsRNA in P-MS iNSCs attenuated senescence and innate immune activation, while also dampening the spread of pro- inflammatory responses. My findings suggest that mt-dsRNA serves as a crucial driver of senescence-associated dysfunction in a patient stem cell model of P-MS, highlighting the potential contribution of cytosolic nucleic acid sensing to disease pathobiology and identifying novel therapeutic targets for further investigation. University of Cambridge 2025-05-28 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/389931 embargo 2027-09-25 https://www.repository.cam.ac.uk/bitstreams/a0c3f07b-196c-48ca-b850-3b8621534021/download cd98499ffbe301034988bf8916c396d0 https://www.repository.cam.ac.uk/bitstreams/4912e9f5-442e-4a99-aecc-9d5bb807f2a9/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved Multiple Sclerosis Senescence Neuroinflammation Progressive Multiple Sclerosis Cytosolic Nucleic Acids