PROJECT ABSTRACT This proposal investigates a novel idea to explain how TDP-43 protein pathology is amplified and spread between glia and neurons after initiation of disease. TDP-43 aggregation pathology is a core feature of a suite of neurodegenerative disorders including frontotemporal dementia, Alzheimer’s and amyotrophic lateral sclerosis. We propose and will test the hypothesis that retrotransposons and endogenous retroviruses are both activated by TDP-43 pathology and can be upstream initiators of such pathology. We also will test the idea that these mobile elements contribute a mechanism of inter-cellular spread that could underlie progression of disease. We will use both Drosophila models and mammalian cell culture to test the core features of this proposed model.