Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily targets motor neurons, leading to progressive muscle weakness and paralysis. There is no cure for ALS or the related disorder frontotemporal dementia (FTD), largely because it is unclear which of the many implicated cellular pathways are causative. A growing number of studies have identified damage to the nuclear pore complex (NPC) as a key pathological phenotype in both ALS-diseased tissue and ALS models. This damage is characterized by defective nucleocytoplasmic transport and mislocalization of NPC components (“Nups”) to the cytosol. To examine the fate of mislocalized Nups, our research group has developed a model for NPC disruption whereby we deplete a key structural Nup and track the localization of other Nups. Strikingly, our preliminary data shows that the displaced Nups form aggregates in the endoplasmic reticulum, a process which is dependent on the ER transmembrane protein kinectin. These aggregates accumulate upon depletion of the major autophagy factor Beclin-1, suggesting that the Nups are targeted for ER-coupled autophagy. Together, these findings point to a novel nucleus-to-ER autophagy pathway that may be functioning when Nups are displaced in ALS. Based on this preliminary data, we hypothesize that the cellular motor protein kinesin-1 transports Nups from the nucleus to the ER (Aim 1A), and that this transport process also occurs in a disease-relevant cell culture model (Aim 1B). We further hypothesize that once at the ER, the Nup aggregates are cleared by receptor-mediated autophagy (Aim 2). This work will elucidate basic intracellular trafficking and quality control pathways. More importantly, understanding cellular response to mislocalized Nups may provide a better mechanistic picture of the progression of ALS/FTD.