Neurodegenerative diseases such as Alzheimer’s disease and related disorders, are characterized by progressive decline in cognitive function and neuronal degeneration. A key molecular driver of these diseases is the dysregulation of post-translational modifications (PTMs) including phosphorylation, ubiquitination, acetylation, glycosylation, SUMOylation, and oxidation. Under physiological conditions, PTMs plays important role in regulating protein expression, stability, activity and localization whereas their imbalance contributes to the protein destabilization, misfolding and assembly into toxic aggregates, ultimately driving neuronal dysfunction and death. Moreover, several studies have demonstrated that PTMs modulate critical cellular signaling pathways, such as the PI3K/Akt pathway, further implicating them in the pathogenesis of neurodegenerative diseases. Dysregulation of PTMs often arises from alterations in upstream regulators, including kinases, phosphatases, E3 ubiquitin ligases, deacetylases, and other modifying enzymes. Importantly, PTMs are highly dynamic and reversible, making them attractive targets for therapeutic intervention. Understanding how specific PTMs influence proteostasis and signaling networks provides valuable insights into disease mechanisms and offers potential avenues for novel treatments.

This Research Topic aims to explore how post-translational modifications (PTMs) contribute to the onset and progression of neurodegenerative disorders and how they can be leveraged for therapeutic interventions. Despite recent advances in identifying disease-associated PTMs in proteins such as tau, α-synuclein, and TDP-43, the interplay among multiple modifications and their functional consequences remains poorly understood. This collection seeks to highlight studies investigating the function, dysregulation, and crosstalk of PTMs, as well as their impact on protein aggregation, proteostasis, and neuronal survival, alongside the development of novel technologies and therapeutic approaches. By integrating molecular, cellular, and translational perspectives, this Research Topic will provide a comprehensive view of PTM-driven mechanisms in neurodegeneration and identify actionable strategies for therapy.

We welcome original research, reviews, and perspectives addressing post-translational regulation in neurodegenerative diseases. Topics of interest include, but are not limited to:

• Mechanistic roles of PTMs including phosphorylation, ubiquitination, SUMOylation, acetylation in brain aging and neurodegenerative disorders.

• PTM mediated regulation of protein folding, trafficking, phase separation, aggregation, and clearance (Ubiquitin protesome system, autophagy/lysosome, chaperones, Unfolded protein response).

• Dysregulation of PTM-regulating enzymes—such as kinases, phosphatases, E3 ubiquitin ligases, and deacetylases—and their contribution to impaired proteostasis, aberrant signaling, and neuronal degeneration.

• Crosstalk between multiple PTMs and how combinatorial modifications shape neuronal signaling networks and disease outcomes.

• Novel technologies and methodologies including proteomics for studying PTMs in vitro, in vivo, and in patient-derived models.

• Model systems including iPSC-derived neurons and organoids, in vivo models, and human biospecimens.

• Computational modeling, network analysis, and AI approaches to PTM–proteostasis–signaling integration.

• Therapeutic strategies targeting deregulated PTM pathways, including small molecules, PROTACs, Biodegraders, or gene-editing approaches.

Submissions integrating molecular mechanisms with translational or therapeutic relevance are especially encouraged. This Research Topic aims to provide a comprehensive platform for advancing our understanding of PTMs in neurodegeneration and their potential as therapeutic targets.

Are you interested in contributing a manuscript to this Research Topic?

Post-translational Modifications and the Regulation of Proteostasis and Cell Signaling in Neurodegenerative Diseases