TDP-43 proteinopathies are a group of diseases that include amyotrophic lateral sclerosis (ALS). TDP-43 proteinopathies are defined by loss-of-function of DNA- and RNA binding protein, TDP-43. Investigation into TDP-43 has uncovered potential mechanisms of TDP-43 proteinopathy pathogenesis. TDP-43 has been shown to bind to endogenous retrovirus (ERV) sequences in the human genome, and both TDP-43 knockdown and overexpression promote ERV dysregulation in vitro and in vivo. ERVs offer new perspective on genomic dysregulation and disease. Transposable elements – artifacts of viral integrations spanning hundreds of millions of years of evolution – make up 45% of the human genome. 8% of the human genome, ERVs are the most recent retrotransposon insertions, the youngest integration occurring <6M years ago. ERV loci exhibit polymorphism across human populations due to replication and recombination, thus contributing to genomic diversity. Young ERVs contain intact proviral elements, i.e. LTRs, gag, pol, and env open reading frames, which may dysregulate gene expression and initiate inflammation in disease. Current tools fail to quantify ERV locus expression and define ERV transcript structure. Short-read RNA-sequencing (RNA-seq) is a technology capable of mapping unique 200bp reads to the genome with high accuracy. However, short-read RNA-seq is for ERVs is flawed due to their repetitive genomic content and large average size (7kb). Conflicting reports on ERV dysregulation in ALS between annotations and algorithms highlight the failures of current tools to 1) reliably map ERV transcripts to their loci and 2) denote ERV transcript structure. Long-read RNA-seq offers a solution for these limitations by generating reads up to 10kb long, thereby increasing ERV transcript mapability. Using long-read RNA-seq, I will be able to analyze ERV expression in the transcriptome with high confidence and at a higher resolution than previously possible. I propose to use whole transcriptome long-read RNA-seq to profile ERV splicing behavior in TDP-43 proteinopathies.