Advances in the Study of Protein Deamidation: Unveiling Its Influence on Aging, Disease Progression, Forensics and Therapeutic Efficacy

Abstract

Protein deamidation, a nonenzymatic post-translational modification that converts asparagine and glutamine residues into their acidic forms, such as aspartic acid, iso-aspartic acid, or glutamic acid, has emerged as a pivotal process affecting protein stability and function. Once considered a minor biochemical occurrence, deamidation is now recognized for its significant role in aging, age-associated diseases, disease progression, cancer, and therapeutic efficacy. This review explores the recent advances in understanding protein deamidation, its impact on cellular homeostasis, protein misfolding, and age-related and chronic diseases including neurodegeneration and cancer. The study also highlights the challenges posed by deamidation in biopharmaceuticals, where it compromises therapeutic stability and efficacy. Advancements in state-of-the-art analytical techniques and computational approaches for identifying deamidation sites and predicting deamidation-prone regions are discussed, along with deeper insights into how deamidation affects protein structure and function. Based on the current insights, this review underscores the dual role of deamidation as both a natural regulatory process and a contributor to pathological states, providing a roadmap for future research in aging biology, disease mechanisms, and therapeutics.

Keywords: aging; biopharmaceuticals; cancer; deamidation; dementia; forensics.

Figure 1

Biological and societal outreach of protein deamidation. Applications of protein deamidation across various disciplines.

Figure 2

Schematic representation of the deamidation-induced neurodegenerative cascade. (A) Deamidation induces protein misfolding and aggregation, evading proteostasis and triggering microglial activation, which drives neuroinflammation and neuronal dysfunction. (B) The unified theory of neurodegeneration pathogenesis (adopted from Davis Joseph [70]). Axon deamidation, establishes the link between the four fields of deamidation (Step A), translational control (Step B), neurodegenerative diseases (Options 1 to 4), and oxidative stress (Option 4).

Figure 3

Impact of protein deamidation on various cellular processes and the proposed mechanism of tumor progression.