The Nuclear Pore Hypothesis of Neurodegeneration

The Nuclear Pore Hypothesis of Neurodegeneration: Dysfunction in the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) machinery may be a common mechanism underling the majority of neurodegenerative diseases and what may distinguish one disease from another are the unique components of the NPC and NCT machinery that are affected. The type of neurodegeneration produced may depend on the specific NPC and NCT components affected, the unique or overlapping cargo they are responsible for trafficking, and the cell or tissue type’s dependence on those mistrafficked cargo. In order for any cell to function properly, it is imperative that RNA and protein be efficiently and selectively exchanged between the nucleus and the cytoplasm. This is critical for signal transduction and is especially arduous for neurons due to their highly polarized biology. Efficient regulation of this process is imperative for neuronal plasticity and overall survival. This critical task is achieved by the ~2000 NPCs that span the entire nuclear envelope and serve as the main gateway of the nucleus. Each NPC consists of multiple copies of 30 different proteins called nucleoporins (NUP) and mutations in various NUPs result in tissue‐specific diseases. Additionally, some of the longest‐lived proteins in the mammalian brain are specific NUPs and may represent the “weakest link” in the aging proteome. In this thesis, we provide evidence demonstrating that the NPC and NCT machinery is severely disrupted in models of Huntington’s disease, C9orf72-ALS/FTD, sporadic ALS, and Alzheimer’s disease using induced pluripotent stem cell-derived neurons from human patients, human postmortem brain tissue, various mouse and fly models, primary neurons and employing techniques such as immunofluorescence, confocal imaging, siRNA technology, proteomics, and RNA-seq. We demonstrate that several pathways responsible for this disruption include toxic neurodegenerative disease protein and RNA species, stress granule dynamics and O-GlcNAcylation. Finally, we demonstrate that we can rescue these NPC and NCT defects and mitigate neurotoxicity by targeting this pathway through the overexpression of NUPs or NCT machinery or treatment with drugs that prevent aberrant NUP biology including a small molecule inhibitor of nuclear export and a small molecular inhibitor that increases levels of O-GlcNAc