Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function.

ABSTRACT: Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation-deficiencies cause selective neurological defects is unknown. Using murine UFM1-deficient neurons, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81C-expressing neurons display distinct respons

SUBMITTER: Catarina Perdigao 

PROVIDER: S-SCDT-10_1038-S44321-026-00389-6 | biostudies-other |

REPOSITORIES: biostudies-other