Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the selective loss of subsets of neurons in the central nervous system (CNS). While increasing evidence suggests a combination of both genetic and environmental factors as the cause of both AD and PD, the molecular etiology underlying the pathogenesis of these diseases remains largely unknown. The gene Suppressor enhancer lin-12 1-Like (SEL1L) is widely known to encode an endoplasmic reticulum (ER) membrane protein and is highly expressed in CNS neurons. To investigate the potential association between neurodegeneration and dysfunction of SEL1L, we generated and characterized mice with a neuron-specific knockout of SEL1L (Sel1l-NKO). Sel1l-NKO mice have an average lifespan of 8-10 weeks and show significant growth retardation. These mice progressively developed motor dysfunction, manifested by abnormal limb clasping, impaired gross and fine motor coordination, and loss of body strength. In addition, Sel1l-NKO mice exhibited broad deficits in spatial memory and learning. Immunohistological analysis revealed a perturbed dendritic network in the cerebral cortex. Cultured SEL1L-deficient primary neurons of the cerebral cortex displayed impaired dendritic growth. Furthermore, Fluoro-Jade C staining revealed an increased number of degenerating neurons in Sel1l-NKO mice. Altogether, these behavioral and cellular defects indicate that SEL1L deficiency results in neurological disorders. The molecular mechanism behind these neurological disorders is unclear. We therefore investigated the protein expression pattern of the Sel1l-NKO brain to identify the mechanistic alternation in the absence of SEL1L. The results show that SEL1L deficiency induced disruption of ER homeostasis and activated the unfolded protein response (UPR), an adaptive response to misfolded protein aggregation. Unexpectedly, we found elevated levels of phosphorylated microtubule tau protein (p-tau), a pathological characteristic of many neurodegenerative diseases. Our data suggest that a brachial downstream gene of UPR, c-Jun N-terminal kinases (JNK), might be the major tau kinase that induces tau phosphorylation in Sel1l-NKO mice. To further investigate the role of UPR in these neurological disorders, an inhibitor of the eIF2alpha kinase (PERK) branch of the UPR was administrated to Sel1l-NKO mice, which slightly improved their motor function performance. Collectively, our data suggest that dysfunction of SEL1L, via sustained UPR and tau pathology, induces neurotoxicity. ii