Comprehensive review of the UFMylation post‑translational modification system that synthesizes current evidence linking impaired UFMylation to neurodegenerative pathologies, including modulation of tau and α‑synuclein, and proposes UFMylation as a potential therapeutic and biomarker axis.

Highlights a novel, targetable PTM pathway (UFM1 enzymatic cascade) connected to α‑synuclein and tau biology, providing mechanistic hypotheses and biomarker leads that could be translated into Parkinson’s therapeutics after focused experimental validation.

UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.