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ResearchIn-Press PreviewCell biologyNeuroscience Open Access | 10.1172/JCI196819

Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice

Mauricio Torres,1 You Lu,2 Brent Pederson,2 Hui Wang,1 Anna Gretzinger,2 Liangguang Lin,1 Jiwon Hwang,2 Xinxin Chen,1 Alan C. Rupp,2 Abigail J. Tomlinson,2 Andrew J. Scott,3 Zhen Zhao,4 Daniel R. Wahl,3 Martin Myers, Jr,2 Costas A. Lyssiotis,2 and Ling Qi1

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Torres, M. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Lu, Y. in: PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

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1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Wang, H. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

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1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Lin, L. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Hwang, J. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Chen, X. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Rupp, A. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

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1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Scott, A. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Zhao, Z. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Wahl, D. in: PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Myers, Jr, M. in: PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Lyssiotis, C. in: PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

3Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America

4Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

Find articles by Qi, L. in: PubMed | Google Scholar |

Published February 19, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI196819.
Copyright © 2026, Torres et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 19, 2026 - Version history
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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.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplemental Video 1: Terminal-stage Sel1LSynCre mouse exhibiting pronounced tremor. A 10-week-old Sel1LSynCre male mouse, alongside two Sel1Lf/f control littermates, was recorded while consuming soft gel food in its home cage at the terminal stage. Note the persistent tremor observed during eating and grooming behavior.

View Supplemental video 2: Hindlimb clasping reflex in Sel1Lf/f and Sel1LSynCre mice at 2 weeks of age. The hindlimb clasping reflex was assessed via tail suspension in control (Sel1Lf/f) and neuron-specific Sel1L knockout (Sel1LSynCre) mice at postnatal day 14. Healthy mice typically extend their hindlimbs outward when suspended by the tail. In contrast, Sel1LSynCre mice exhibit an abnormal clasping phenotype, retracting their hindlimbs toward the midline of the body.

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Version history
  • Version 1 (February 19, 2026): In-Press Preview
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