New Quality Control Mechanism Protecting Nerve Cells Discovered

A joint research group, including Professor Masaaki Komatsu from the Department of Organ and Cell Physiology, Graduate School of Medicine, Juntendo University, Professor Nobuo N. Noda from the Institute for Genetic Medicine, Hokkaido University, and Professor Toshifumi Inada from the Institute of Medical Science, The University of Tokyo, has elucidated a new "protein quality control system" that operates on the endoplasmic reticulum.

Inside cells, "protein factories" called ribosomes produce proteins essential for life. However, abnormalities during protein production can cause severe stress to the cell. Nerve cells are particularly vulnerable to such abnormalities, and the breakdown of their quality control mechanisms is known to lead to neurodevelopmental disorders and neurodegenerative diseases.

The research group discovered that the UFSP2-ODR4 enzyme complex, which functions on the endoplasmic reticulum, protects nerve cells by monitoring abnormalities arising from the protein factories (ribosomes) and performing quality control.

Furthermore, analyses using genetically modified mice and cells derived from patients with neurodevelopmental disorders revealed that the failure of this mechanism leads to neuronal cell death and microcephaly.

These findings represent a significant advancement in understanding the pathogenesis of neurodevelopmental disorders and hold promise for the development of new therapeutic strategies.

This paper was published online in Molecular Cell on July 9, 2026.

Key Findings of This Research:

● Discovered a new "intracellular quality control system" that protects nerve cells.

● Elucidated that the UFSP2-ODR4 enzyme complex monitors abnormalities in protein factories (ribosomes).

● Discovered that abnormalities in this mechanism lead to microcephaly and neurodevelopmental disorders.

Background

Inside cells, "protein factories" called ribosomes produce proteins essential for life. In particular, on the surface of intracellular organelles called the endoplasmic reticulum, proteins necessary for nerve cell development and signal transmission are actively synthesized.

However, abnormalities in these factories can lead to incomplete proteins or abnormal ribosomes, placing a significant burden on the cell. Nerve cells are especially sensitive to such abnormalities, and it is known that the malfunction of quality control mechanisms can lead to neurodevelopmental disorders and neurodegenerative diseases.

Cells are equipped with quality control systems to monitor and address these abnormalities. However, much remains unknown about how quality control on the endoplasmic reticulum is regulated.

Content

Through analyses using cells, mice, and patient-derived cells, the research group discovered that the UFSP2-ODR4 enzyme complex, operating on the endoplasmic reticulum, is responsible for the quality control of protein factories (ribosomes) and protects nerve cells. This enzyme complex protects nerve cells by removing abnormal proteins and returning ribosomes to a reusable state (Figure 1). Furthermore, using genetically modified mice and cells derived from patients with neurodevelopmental disorders, they clarified that the breakdown of this mechanism leads to neuronal cell death and microcephaly. They also found that in patients with neurodevelopmental disorders, the regulation of protein factories is disrupted due to abnormalities in this quality control system (Figure 1).

Future Prospects

These findings reveal a new quality control mechanism that protects nerve cells and represent a significant step forward in understanding the pathology of neurodevelopmental disorders. Future applications are expected in the development of new therapeutic strategies targeting this quality control system, as well as in diagnostic and therapeutic strategies for neurodevelopmental disorders.

Figure 1: Protein factory quality control mechanism elucidated in this study.

When abnormalities occur in ribosomes (protein factories) synthesizing proteins on the endoplasmic reticulum, the UFSP2-ODR4 complex performs quality control, removing abnormal proteins and returning ribosomes to a reusable state. This maintains the homeostasis of nerve cells. Conversely, if the function of the UFSP2-ODR4 complex is lost, the quality control mechanism breaks down, leading to neurodevelopmental disorders accompanied by neuronal cell death and microcephaly.

Glossary

*1 Endoplasmic reticulum: A structure within the cell that plays a crucial role in protein synthesis and quality control.

*2 Protein quality control system: A mechanism within the cell that monitors and removes abnormal proteins to prevent their production or accumulation.

*3 Ribosome: A "protein factory" within the cell that produces proteins. It reads genetic information and synthesizes proteins necessary for life activities.

*4 UFSP2-ODR4 enzyme complex: An enzyme formed by the combination of two proteins, UFSP2 and ODR4. It functions on the endoplasmic reticulum and plays a role in protecting nerve cells by supporting the quality control of protein factories (ribosomes).

Original Paper

This research was published online in Molecular Cell on July 9, 2026.

Title: The UFSP2–ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis

Japanese Title Translation: Elucidation of the Spatial Control Mechanism of UFM1 Deconjugation by the UFSP2-ODR4 Enzyme Complex and its Role in Maintaining Neuronal Proteostasis

Authors: Gaoxin Mao, Sota Ito, Ryosuke Ishimura, Jun-ichi Sakamaki, Ryohei Sasaki, Takefumi Uemura, Kei-ichi Ishikawa, Satoko Komatsu-Hirota, Wado Akamatsu, Manabu Abe, Satoshi Waguri, Sunita Bijarnia-Mahay, Nobuo N. Noda, Toshifumi Inada, Masaaki Komatsu

Authors (Japanese Notation): 毛 高鑫1), 伊藤 壮太2), 石村 亮輔1), 坂巻 純一1), 佐々木 諒平3), 植村 武文4), 石川 景一5), 小松−廣田 聡子1), 赤松 和土5), 阿部 学6), 和栗 聡4), Sunita Bijarnia-Mahay 7), 野田 展生3), 稲田 利文2), 小松 雅明1)8)

Author Affiliations: 1) Department of Organ and Cell Physiology, Graduate School of Medicine, Juntendo University, 2) Department of Molecular Biology, Institute of Medical Science, The University of Tokyo, 3) Department of Molecular Genetics, Institute for Genetic Medicine, Hokkaido University, 4) Department of Anatomy and Histology, Fukushima Medical University School of Medicine, 5) Center for Genomics and Regenerative Medicine, Graduate School of Medicine, Juntendo University, 6) Department of Physiology and Regenerative Medicine, Brain Research Institute, Niigata University, 7) Institute of Medical Genetics & Genomics Sir Ganga Ram Hospital, 8) Autophagy Research Center, Graduate School of Medicine, Juntendo University

DOI: https://doi.org/10.1016/j.molcel.2026.06.026

This research was supported by JSPS KAKENHI grants JP23K20044, JP24H00060, JP25H01323, JP24H01901, JP23K27134, JP23K06065, JP25H01419, JP25H00966, JP25H01320, JP25H0132, JP25H00315, P22H04926, and AMED grants JP22gm1410004h0003, JP21gm6410019h0001, JST-CREST JPMJCR20E3, the Takeda Science Foundation, the Uehara Memorial Life Science Foundation, the Kobayashi Foundation, and the Mitsubishi Foundation, and was conducted as a collaborative project with multiple institutions.

We express our sincere gratitude to all those who cooperated in this research.