Thursday, April 3, 2025
4/3/2025
NUP50 as a modifier and risk factor for TDP-43 pathology in FTD/ALS - The cytoplasmic mislocalization and accumulation of insoluble and misfolded RNA- binding protein TDP-43 is the neuropathological hallmark of the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) disease spectrum but is also commonly found in Alzheimer’s disease (AD) and other AD-related dementias (ADRDs), marking TDP-43 mislocalization as a key pathomechanism and high priority target for therapy development. Previous studies from our lab and others have established nuclear pore defects and impaired protein import and RNA export, as a common hallmark of FTD/ALS and other age-related neurodegenerative diseases. While there is growing evidence that perturbations in the nucleocytoplasmic transport machinery are linked to TDP-43 pathology, the causal relationship between intracellular transport pathways and disease pathogenesis is not well understood. As prior research to support the premise of this proposal, we have discovered that expression of the nucleoporin NUP50 in FTD/ALS models can restore solubility and nuclear localization of TDP-43, suggesting an important role for NUP50 in the disease process. This premise is further supported by the recent discovery of rare NUP50 variants as a risk factor for ALS, and a critical role for NUP50 in neuronal survival. These findings lead us to hypothesize that NUP50 serves in a non-canonical role in reducing protein mislocalization and aggregation, while its deficiency in FTD/ALS may lead to increased TDP-43 pathology, suggesting NUP50 as a promising target for therapy development. To test this hypothesis, we will use TDP-43 cellular, organotypic and animal models, patient-derived and induced pluripotent stem cell (iPSC)-derived neurons, in combination with mass spectrometry (MS)-based quantitative proteomics and immunohistochemistry in human brain tissue, to elucidate how NUP50 can reduce TDP-43 pathology, and how ALS/FTD-associated mutations in NUP50 contribute towards TDP-43 pathology. In Aim 1 we will methodically investigate the effect of NUP50 on aberrant TDP-43 phase transition and mislocalization and establish the role of structural domains and associated proteins for a mechanistic understanding of this activity in vitro. In Aim 2 we will determine the effect of NUP50 on TDP-43-dependent neurodegeneration in FTD/ALS mouse models, to evaluate NUP50 and associated proteins as a potential therapeutic targe in vivo. In Aim 3, we will establish the role of NUP50 in human TDP-43 proteinopathies, by testing the effect of NUP50 deficiency and disease-associated NUP50 variants on TDP-43 pathology and assessing the abundance and localization of NUP50 in FTD/ALS and ADRD autopsy brain tissue. Our findings will impact the field by providing a detailed mechanistic understanding of how NUP50 expression can impact TDP-43 pathology in disease models, and by establishing the role of NUP50 in the disease process and validating it as a potential therapeutic target in FTD/ALS and other ADRDs.
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