The many connections of UFMylation with Alzheimer's disease: a comprehensive review

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder that is characterized by the accumulation of pathologic tau and beta-amyloid proteins. UFMylation is an emerging ubiquitin-like post-translational modification that is crucial for healthy brain development. The UFM1 cascade was recently identified as a major modifier of tau aggregation in vitro and in vivo. Moreover, post-mortem AD brain shows pronounced alterations of UFMylation that are significantly associated with pathological tau, suggesting UFM1 might indeed be a modifier of human disease. However, the link between AD and UFMylation is yet to be fully explored. Interestingly, the UFMylation cascade is known to play important roles for several pathways that are known to be altered in AD, such as the DNA damage response, ER homeostasis, autophagy and the immune response. This review discusses the many connections between UFMylation with AD pathogenesis, emphasizing the role of UFMylation in these pathways and their abnormalities in AD. Understanding these connections is important to elucidate molecular mechanisms how UFM1 may impact AD and to uncover novel therapeutic strategies targeting UFMylation pathways for disease modification.

Fig. 1

Key reported biological functions of UFMylation. The UFMylation pathway is known to play a role in various physiological processes including DNA damage response (DDR), endoplasmic reticulum (ER) stress response, regulating autophagy functions, and influencing the immune response. There is also evidence suggesting its involvement in mitochondrial and ribosome-associated protein quality controls. Dysregulation of UFMylation has been associated with developmental disorders, particularly neurodevelopmental disorders, various types of cancers, and it may also have a potential link with neurodegenerative diseases like Alzheimer’s Disease (AD). Reported proteins modified by UFM1 have been categorized based on the pathways they are involved in. Proteins labeled with “*” have been connected with AD

Fig. 2

Cascade of the UFMylation and deUFMylation processes. The UFMylation pathway initiates with the precursor of UFM1 (pro-UFM). In the first step, UFM1-specific cysteine proteases, UFSP1 and UFSP2, enzymes cleave two amino acids from pro-UFM, resulting in mature UFM1 that exposes a glycine residue. Subsequently, UBA5 activates this mature UFM1. Once activated, UFM1 is handed over to UFC1. The critical step of ligating UFM1 to its target proteins is conducted by UFL1, aided by two adaptor proteins, DDRGK1 and CDK5RAP3, which expand the range of potential substrates for UFL1. The UFMylation process is reversible, with UFSP1/2 cleaving UFM1 from its substrates for recycling. Abbreviations: UFC1, ubiquitin fold-modifier conjugating enzyme 1; UFL1, ubiquitin fold-modifier specific ligase 1; UFM1, ubiquitin-fold modifier 1; VGSC: valine–glycine–serine–cysteine amino acids