Dysregulation of UFMylation pathway in Alzheimer’s disease

Abstract

AbstractBackgroundNeuropathologically, Alzheimer’s disease (AD) is characterized by the presence of senile plaques composed of beta‐amyloid (Aβ) and neurofibrillary tangles made of hyperphosphorylated tau. Aβ and p‐tau have been shown to impact endoplasmic reticulum homeostasis, DNA damage response and autophagic functions. Intriguingly, alterations in these systems have also been connected to dysfunctions in UFMylation, a ubiquitin‐like posttranslational modification. Analogous to ubiquitin, UFM1, is conjugated to substrates via a catalytic cascade involving UFM1‐specific set of E1 (UBA5), E2 (UFC1), and a complex that consists of E3 ligase (UFL1), DDRGK1 and CDK5RAP3. UFMylation is reversible, and this is mediated by UFSP2. The UFMylation pathway is essential for brain development as complete loss of function of any of its components result in severe neurodevelopmental disorders. However, alterations in UFMylation and their role in and significance for age‐related AD remains unknown.MethodWe performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2, tau, p‐tau and other UFMylation pathway components in human post‐mortem brain. Analyses were performed with RIPA‐ and 2% SDS‐soluble fraction from frontal cortex. To validate our finding in human tissues, we knocked out UFM1 and UFSP2 in ReN cells, a neural progenitor cell model that has already been used to study AD and that can be terminally differentiated in neurons.ResultWe found a significant reduction of RIPA UFSP2, but an increase of RIPA and SDS UFM1 in AD compared to controls. Strikingly, RIPA UFSP2 had a strong negative correlation with both RIPA and SDS UFM1. Furthermore. UFM1 was significantly increased in UFSP2‐KO neurons compared to WT, mirroring the negative correlation between UFM1 and UFSP2 observed in human brain. In addition, RIPA and SDS UFM1 had a strong positive correlation with p‐tau, indicating that dysfunctional UFMylation might play an important role for disease pathogenesis.ConclusionReduction of RIPA soluble UFSP2 in human AD frontal cortex might result in the abnormal accumulation of UFM1 and this might further facilitate the AD pathogenesis. Because of its role for several central AD‐relevant pathways, the UFMylation pathway might be a potential therapeutic target for AD.