Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder characterized by the accumulation of inclusion bodies within the nucleus of cells. The major neurotoxic component in inclusions has been identified as poly-Glycine peptide translated from the GGC repeated expansion sequence within NOTCH2NLC gene. However, the precise mechanisms underlying their formation, subcellular dynamics, and contribution to neurotoxicity remain unclear. polyG is immunoreactive for several markers (p62 and ubiquitin) associated with autophagic degradation pathways, suggesting that polyG exerts neurotoxicity by attacking the autophagic machinery. Notably, p62 is a nucleocytoplasmic protein. In addition to its role as an autophagic adaptor, nuclear p62 has been implied in accelerating protein aggregation, further sequestering the toxic proteins. Together, we hypothesize that p62 exerts a dual neuroprotective role against polyG toxicity, thereby mitigating the progression of NIID. NIID patient samples show elevated autophagy markers (e.g., p62, LC3-II/I ratio), indicating induced but insufficient autophagy to clear uN2CpolyG aggregates. Rapamycin treatment in NIID cells and Drosophila models enhances uN2CpolyG clearance and improves neuronal function. uN2CpolyG accumulates in both the cytoplasm and nucleus, initially localizing to the cytoplasm before forming insoluble nuclear inclusions. p62 knockdown delays polyG inclusion formation but increases total polyG accumulation, suggesting p62 facilitates polyG aggregation/clearance. This knockdown also worsens locomotor defects in Drosophila, highlighting p62's role in mitigating polyG neurotoxicity. Future work will investigate p62's distinct nuclear and cytoplasmic roles to understand how polyG toxicity varies by subcellular localization and molecular state.