Wagen, Aaron Zvi; (2025) From peripheral immune activation to central protein aggregation: a genomic investigation of immune mechanisms in neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The immune system is increasingly implicated in the pathogenesis of neurodegener- ative disease. The protein aggregation and neuronal damage that typify these condi- tions is often associated with immune activation and inflammation both in the cen- tral nervous system (CNS), and also peripherally. There is also suggestive evidence that this peripheral response is more than an echo of central processes, with clinical and epidemiologic data suggesting that peripheral changes may precede immune activation centrally, and may mediate environmental risk of these diseases. This thesis utilises genomic approaches to interrogate the mechanisms whereby immune responses mediate neurodegeneration, both peripherally and within the CNS. First I utilise genome wide association studies and functional genomic annotations from African, East Asian and European ancestries to show that the expression of genes that cause neurodegenerative diseases is enriched in peripheral innate immune cells, and that this expression mediates the risk of disease in an ancestry-specific manner. I then explore adenosine-to-inosine (A-to-I) RNA editing, an innate immune mech- anism that can have broad transcriptomic effects through editing RNA. I develop an analysis pipeline to show that an astrocytic inflammatory state induced by alpha- synuclein oligomers is associated with an increase in RNA editing site number, rate and a change in genic location, in a human stem-cell derived model. Finally, I apply the pipeline to post-mortem human brain data in ageing and disease, show- ing distinct patterns of A-to-I editing in these conditions. These findings illustrate specific mechanisms whereby the immune system mediates neurodegenerative dis- eases, identifying possible pathways to target therapeutically, and emphasising the importance of integrating the study of immunity and neurodegeneration.

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