The overarching goal of this supplement proposal is to support a graduate student from an underrepresented population to determine the role of TDP43 proteinopathy and endogenous retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal dementia and Alzheimer’s and related dementia, using the established approaches and strategies from the parent grant. In the Drosophila system, it has been established that ERVs and DNA damage play a causal role in cell-autonomous glial cell death and in non-autonomous toxicity to nearby neurons. Although the impacts of ERVs/RTEs have been described in Drosophila and increased levels of ERVs/RTEs have been measured in human tissues, there are yet no tests of this hypothesis in the initiation and progression of disease during development and aging in a mammalian model of ALS or FTD. Here we propose essential tests of our novel hypothesis to establish the temporal, spatial, and cell-specific impacts of TDP-43 pathology on ERV/RTE expression and on disease progression and spread within the CNS. In addition, we will provide a PLATFORM that will enable the field to uncover cellular mechanisms by which RTEs/ERVs may contribute, and to do so in a vertebrate model. We are investigating a novel integrative in vivo experimental approach with the power to provide insights into RTE biology, neurodegenerative phenotypes, and focal and longitudinal perturbations in a vertebrate model of TDP-43-ALS/ADRD. The low-expressing TDP-43 mouse strains in Aim 1 of the parent grant are mostly completed under another PhD student, but Ariel Nieves will continue and complete these experiments. The main work for Ariel will be to incorporate tools that we have established in our laboratory for sparse expression (Adeno-associated viruses, AAV) in the rodent system, enabling us to manipulate gene function in specific and focally initiated populations of cells (neurons, glia), and to delineate effects on nearby, unperturbed cells or tissues.