The Role of SEL1L in Neurodegeneration

Abstract

Neurodegenerative diseases such as Alzheimer¡¦s disease (AD) and Parkinson¡¦s diseases (PD) are characterized by the selective loss of subsets of neurons in the central nervous system (CNS). While increasing evidence reveals a combinatory causes involving both genetics and environmental factors, the molecular etiology underlying the pathogenesis of both AD and PD remains incompletely understood. Suppressor enhancer lin‐12 1 Like (SEL1L), which encodes an endoplasmic reticulum (ER) membrane protein, is highly expressed in the CNS neurons. To investigate the potential association between neurodegeneration and dysfunction of SEL1L, we generated and characterized mice with 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 develop motor dysfunction, manifested by abnormal limb clasping, impaired motor coordination, and loss of body strength. In addition, Sel1l‐ NKO mice exhibit spatial memory deficit. Immunohistological analysis reveals a perturbed dendritic network in the cerebral cortex. Cultured SEL1L‐deficient cerebral cortical primary neurons display an impaired dendritic growth. Together, these results indicate that dysregulation or dysfunction of SEL1L due to genetic mutations or aging may be implicated in the pathogenesis of neuodegenerative disorders in humans.