Novel Role of SEL1L-HRD1 ERAD in Neurodevelopment

Novel Role of SEL1L-HRD1 ERAD in Neurodevelopment ABSTRACT Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a principal mechanism for the recruitment and retro-translocation of misfolded ER proteins for cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex represents the most conserved branch of ERAD, where SEL1L is an obligatory cofactor for the E3 ligase HRD1. Despite recent advances in mouse models, its relevance and significance in humans remained largely unexplored. Recently, we identified four bi-allelic SEL1L and HRD1 hypomorphic variants from 11 human patients presenting with moderate to severe intellectual disability, microcephaly, developmental delay and locomotor dysfunction starting in infancy, collectively termed ERAD-associated neurodevelopmental disorder with onset in infancy (ENDI). This indicates a critical role for SEL1L-HRD1 ERAD in neurodevelopment. Our preliminary data showed that mice expressing a hypomorphic SEL1L variant (Sel1LS658P) exhibit growth retardation, microcephaly, hindlimb clasping, and locomotor dysfunction, closely mirroring the symptoms of ENDI patients. Notably, E16.5 Sel1LS658P embryos exhibited a thinner cortex and disorganized cortical structure, pointing to a possible role of SEL1L-HRD1 ERAD in corticogenesis. Mechanistically, using a non-biased proteomics screen, we found that Astrotactin 1 (ASTN1), a neuronal adhesion molecule required for glial-guided migration of young postmitotic neuroblasts, interacts with SEL1L and is a putative ERAD substrate. Based on these findings, I hypothesize that SEL1L-HRD1 ERAD plays a critical role in neurodevelopment, as least in part, by regulating the biogenesis of the neuron migration-related adhesion molecule ASTN1 in the ER. Using various mouse models powered by state-of-the-art imaging and biochemical techniques, I will accomplish the following two Aims: Aim 1. Determine the (patho)physiological importance of SEL1L-HRD1 ERAD in neurodevelopment; Aim 2. Delineate the molecular mechanism of SEL1L-HRD1 ERAD in neurodevelopment. This study will not only define a new ER quality-control pathway in neurodevelopment and elucidate new regulatory mechanism underlying the biogenesis of a key neuron migration-related adhesion molecule, but also provide a framework for the future study on SEL1L-HRD1 ERAD in various complex brain functions and disorders. The outlined career development plan, including hands-on training, coursework, and meetings/seminars, will allow me to achieve my long-term goal of becoming an independent investigator in the interdisciplinary cell biology-neuroscience fields. Project Number: 1K99HD118580-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Huilun Wang | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $131,166 | Activity Code: K99 | Study Section: Developmental Biology Study Section[CHHD-C] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HD11858001A1