Investigating the mechanism of UPF1-mediated rescue of TDP-43-based models of ALS and FTD

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PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to paralysis and death. There are no available disease-modifying drugs. In 95% of individuals with ALS, affected neurons exhibit cytoplasmic accumulation of TDP-43 (transactive response element DNA/RNA binding protein, 43 kDa). TDP-43 is a ubiquitously expressed splicing factor that is normally localized to the nucleus. In cellular and animal model systems, overexpression of TDP-43 results not only in neurodegeneration, but also TDP-43 cytosolic mislocalization and aggregation, recapitulating key pathologic changes seen in humans. Mutations in the genes encoding TDP-43 (TARDBP) and several similar RNA-binding proteins (RBPs) (e.g. FUS, HNRNPA2B1, MATR3) cause familial ALS as well as the related, often comorbid disease frontotemporal dementia (FTD). How aberrant RBP function may cause ALS and FTD is an ongoing area of research; nevertheless, several pieces of evidence suggest that global disruption of RNA splicing and stability is a central theme. We and others determined that overexpression of the RNA helicase Up-frameshift 1 (UPF1) ameliorates toxicity in both in vivo and in vitro models of TDP43 and FUS toxicity. This proposal seeks to elucidate the mechanism of UPF1-mediated neuroprotection, particularly in models of TDP-43 toxicity. UPF1 is an obligate component of nonsense-mediated decay (NMD), a vital RNA surveillance program. Since the toxicity of TDP-43 dysregulation is strongly linked to its ability to bind RNA, the proposal focuses on the potential interactions between UPF1 and TDP-43 substrates. I hypothesize that UPF1 rescues TDP-43 toxicity by (a) facilitating the clearance of mispliced TDP-43 targets through NMD, (b) interfering with the ability of TDP-43 to bind RNA, or a combination of both. These investigations will not only provide me with the opportunity to develop fundamental scientific skills in experimental design, bioinformatics, and communication, but also promise to deliver new insight into the therapeutic potential of UPF1-mediated neuroprotection. Ultimately, these opportunities will be instrumental in my path to independence as a successful neurologist and neuroscientist dedicated to the study of neurological conditions, disease mechanisms, and therapeutic interventions.