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Updated: Feb 25, 2026
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A Scalable, Cell-Based Method for the Functional Assessment of Ube3a Variants
Published on: October 10, 2022
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Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function.
Catarina Perdigão1, Josefa Torres1, Helge M Magnussen2
1Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, Göttingen, Germany.
EMBO Molecular Medicine
|February 23, 2026
Summary
UFMylation is crucial for neuron development and synapse function. This study reveals how UFM1 gene variants cause encephalopathies and explores Trazodone as a potential treatment for these neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Genetic variants affecting UFM1 (UFMylation) lead to encephalopathies.
- UFMylation is vital for endoplasmic reticulum (ER) homeostasis, but its role in neurological defects is unclear.
Purpose of the Study:
- Investigate UFMylation's role in neuronal development and synapse function.
- Elucidate molecular mechanisms underlying UFM1-associated encephalopathies.
- Explore therapeutic interventions for UFM1-related disorders.
Main Methods:
- Studied UFM1-deficient murine neurons and UFM1-R81C variant expression.
- Analyzed ER stress, unfolded protein response (UPR) pathway activation, and protein translation.
- Assessed the effects of wild-type UFM1 and Trazodone treatment.
Main Results:
- UFM1 deficiency impairs neuron development and synapse function, inducing ER stress and reducing protein translation.
- The pathogenic UFM1-R81C variant causes distinct ER stress responses compared to UFM1 loss.
- Trazodone partially restored protein translation and increased synapse numbers in affected neurons.
Conclusions:
- UFMylation is essential for normal neuronal development and function.
- Distinct molecular defects arise from UFM1 loss versus pathogenic variants.
- Trazodone shows therapeutic potential for UFM1-associated encephalopathies by modulating UPR and synaptic deficits.
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