Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival

SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) is essential for protein folding quality control and maintaining homeostasis in the ER. Defects in SEL1L-HRD1 ERAD complex has been linked to early onset of severe neurological syndromes. However, its physiological importance and underlying mechanisms in neurons remain poorly understood. This study established a mouse model with neuron-specific deletion of Sel1L and revealed that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Overall design: Mice carrying the Sel1L flox/flox allele (WT) were crossed with a Synapsin I promoter-driven Cre line, resulting in Sel1L-SynCre (KO) mice with neuron-specific deletion of Sel1L. The cortex and hippocampus were dissected from the brain of 5-week-old WT (n = 2) and KO (n = 2) mice for neuclei prep. The neuclei suspension was subject to fluorescence-activated cell sorting (FACS) and the resulting single-nuclei prep was used for input onto 10x Genomics Chromium system for generating Chromium Single Cell 3' Libraries.