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Publication
Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function
and survival in mice.
Authors Torres M, Lu Y, Pederson B, Wang H, Gretzinger A, Lin L, Hwang J, Chen X, Rupp
AC, Tomlinson AJ, Scott AJ, Zhao Z, Wahl DR, Myers M, Lyssiotis CA, Qi L
Submitted By Submitted Externally on 3/19/2026
Status Published
Journal The Journal of clinical investigation
Year 2026
Date Published 2/19/2026
Volume : Pages Not Specified : Not Specified
PubMed Reference 41712288
Abstract Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex
have been linked to severe neurological syndromes in children, including
neurodevelopmental delay, intellectual disability, motor dysfunction, and early
death. Despite this association, its physiological importance and underlying
mechanisms in neurons remain poorly understood. Here, we show that neuronal
SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor
function, and overall viability. Neuron-specific deletion of Sel1L in mice
(Sel1LSynCre) resulted in growth retardation, severe motor impairments, and
early mortality by 9 weeks of age-mirroring core clinical features observed in
affected patients-despite preserved neuronal numbers and only modest ER stress.
Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics,
revealed significant dysregulation of one-carbon metabolism in ERAD-deficient
brains. This included activation of the serine, folate, and methionine pathways,
accompanied by elevated levels of S-adenosylmethionine and related metabolites,
likely resulted from induction of the integrated stress response (ISR).
Together, these findings uncover a previously unappreciated role for neuronal
SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic
adaptation, providing new insight into the molecular basis of ERAD-related
neurodevelopmental disease.




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