Work

The modifier matrix: emerging roles of ubiquitin-like proteins in Alzheimer’s disease

Year: 2026

Type: review

Abstract: Ubiquitin and ubiquitin-like proteins (UBLs) have emerged as critical regulators of protein homeostasis and cellular signaling, processes that are increasingly recognized as central to the pathogenesis of Alzheimer's disease (AD). This review explores the expanding roles of UBL modifiers, including SUMO, NEDD8, ISG15, UFM1, and ATG8/ATG12, in the development and progression of AD. We discuss how these post-translational modifications influence key pathological features of AD such as amyloid-beta accumulation and neurofibrillary tangles formation, as well as their impact on neuronal function, proteostasis, and neuroinflammation. Recent advances in our understanding of the enzymatic machinery mediating these modifications, and the interplay between different UBL proteins, offer new insights into the molecular mechanisms underlying AD. Furthermore, we highlight emerging therapeutic strategies targeting UBL pathways, which may provide novel avenues for intervention in AD. By integrating current findings, this review underscores the significance of UBL proteins in AD and identifies future directions for research aimed at unraveling their complex roles in neurodegeneration.

Source: Molecular Neurodegeneration Advances

DOI: 10.1186/s44477-026-00031-2

Authors: Tingxiang Yan, Justine Vaquer, Wolfdieter Springer, Fabienne C. Fiesel

Institutions: Mayo Clinic in Florida, Mayo Clinic

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: Alzheimer's Association, Florida Department of Health, National Alzheimer's Coordinating Center