299: UFM1 loss and R81C mutation disrupt neuronal translation, ER stress, and synaptogenesis

Perdigão C et al., EMBO Molecular Medicine, doi:10.1038/s44321-026-00389-6 - In mouse neurons, UFM1 loss or UFM1-R81C expression reduces protein translation, triggers ER stress and PERK activation, impairing dendrite and synapse development. Key terms: UFM1, UFMylation, ER stress, protein translation, Trazodone.

Study Highlights:
Using murine UFM1-deficient neurons generated by conditional knockout and CRISPR/Cas9 in vivo manipulations and lentiviral rescue, the study combined FUNCAT, puromycin labeling, patch-clamp electrophysiology, RNA-seq, mass spectrometry, TEM tomography, and in vitro UFMylation assays. UFM1 loss caused reduced dendrite complexity, a ~70% drop in colocalized synaptic puncta, decreased EPSC amplitudes and RRP size, induction of ER stress and PERK-UPR activation, and a substantial reduction in global protein translation. The UFM1-R81C variant was hypomorphic: it partially rescued morphology and function but showed drastically impaired activation by the E1 enzyme UBA5 and an aggravated ER-stress response to thapsigargin. Pharmacologically, Trazodone normalized translation in UFM1-R81C neurons and increased synapse numbers in both UFM1-KO and UFM1-R81C conditions, linking UPR/translation modulation to phenotypic rescue.

Conclusion:
UFMylation is required for neuronal development and function: UFM1 loss and the UFM1-R81C variant impair protein translation and ER homeostasis, and Trazodone restores translation in UFM1-R81C neurons while increasing synapse numbers.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function

First author:
Perdigão C

Journal:
EMBO Molecular Medicine, doi:10.1038/s44321-026-00389-6

DOI:
10.1038/s44321-026-00389-6

Reference:
Perdigão C, Torres J, Magnussen HM, Koch J, Rudashevskaya E, Moschref F, Fiosins M, Benseler F, Wenger S, Nilsson T, Beuermann S, Bonn S, Rizzoli SO, Kulathu Y, Jahn O, Cooper BH, Ambrozkiewicz MC, Rhee JS, Brose N & Tirard M (2026) Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-026-00389-6

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and experimental findings presented in the episode and mapped them to the paper's results: UFM1 loss causes reduced dendritic complexity and synapses, reduced translation; UFM1-R81C is hypomorphic with reduced UBA5 activation; PERK-UPR activation; Trazodone rescues translation and increas
- transcript topics: UFMylation pathway and enzymes (UFM1, UBA5, UFC1, UFL1); UFM1 loss: neuronal development and synapse reduction; UFM1-R81C variant mechanism; ER stress and PERK-UPR activation; Protein translation assessment (FUNCAT, puromycin); Trazodone rescue effects on translation and synapses

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0

Chapters

• (00:00:20) - Genetics of encephalopathy: the mystery behind the disease
• (00:03:40) - UFM1 defects in the brain
• (00:08:08) - What Happened to Myelation in Tertiary neurons?
• (00:10:49) - Fixing the RA1C mutation in the brain
• (00:15:42) - UFM1 regulates synaptic firing in the brain
• (00:16:41) - A Small Voice for the Cell