PROJECT ABSTRACT: This proposal will test key aspects of the roles of TDP-43 proteinopathy and endogenous retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal dementia and Alzheimer’s and related dementias. This proposal will test, in a mammalian model, the hypothesis that reactivation of retrotransposons (RTEs) is a means for neurodegeneration and dementia through the following actions: (1) TDP-43 toxicity causes RTE activation in neurons and glia, (2) the effects of TDP-43 on RTEs are non-cell autonomous, and (3) RTEs contribute to toxicity and non-cell autonomy. This proposal will also establish a first-ever mammalian platform to investigate TDP- 43 and RTEs in an established neurodegeneration/dementia model, the TDP-43-Q331K mutant mouse. Two complementary approaches will be used to investigate the role of TDP-43 in retrotransposon biology. First, a low-expressing Tg-hTDP-43-Q331K, but not a low-expressing Tg-hTPD43-WT model, develops motor dysfunction and loss of spinal motor neurons. Second, high overexpression of TDP-43 in either neurons or astrocytes through localized AAV brain injections provides the means to investigate non-cell autonomous signaling between neurons and glia. By driving overexpression only in neurons or glia with AAV virus, the effects of TDP-43 pathology on RTE expression will also be determined, and the non-cell autonomous spread of toxic effects between these cell types. Finally, the relationship of soluble oligomerization to the disease phenotypes will be determined, allowing the pursuit of additional translational investigations into the potential use of reverse transcriptase inhibitors and disaggregase compounds for alleviating or delaying progression of disease.