Formation of inclusions containing misfolded and aggregated proteins is a typical pathological feature observed in many neurodegenerative diseases. NF-Y transcription factor regulates expression of chaperones involved in protein folding, and its sequestration and subsequent reduction of chaperone genes expression are shown in polyglutamine diseases including Huntington's disease. These observations lead us to hypothesize the potential significance of NF-Y in neuronal protein homeostasis. Here we show that neuronal inactivation of NF-Y in mouse brain neurons induces progressive neurodegeneration with distinctive ubiqutin/p62 pathology; they are not incorpotated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic increase in smooth ER without inducing ER stress. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including an ER chaperone Grp94 potentially involved in ER disorganization. Thus, disruption of NF-Y-mediated gene transcription induces previously undescribed novel neuropathology accompanying ubiquitin/p62 accumulation on disorganized ER.