Issue 2, 2025

Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases

Abstract

Highly reactive metabolic intermediates and other small molecules frequently react with amino acid side chains, leading to non-enzymatic posttranslational modifications (nPTMs) of proteins. The abundance of these modifications increases under high metabolic activity or stress conditions and can dramatically impact protein structure and function. Although protein quality control mechanisms typically mitigate the effects of these impaired proteins, in long-lived and degradation-resistant proteins, nPTMs accumulate. In some cases, such as cataract development and diabetes, clear links between nPTMs, aging, and disease progression have been established. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, a key question is whether accumulation of nPTMs is a cause or consequence of protein aggregation. This review focuses on major nPTMs found on proteins with central roles in neurodegenerative diseases such as α-synuclein, β-amyloid, and tau. We summarize current knowledge on the formation of these modifications and discuss their potential impact on disease onset and progression. Additionally, we examine what is known to date about how nPTMs impair cellular detoxification, repair, and degradation systems. Finally, we critically discuss the available methodologies to systematically investigate nPTMs at the molecular level and outline suitable approaches to study their effects on protein aggregation. We aim to foster more research into the role of nPTMs in neurodegeneration by adapting methodologies that have proven successful in studying enzymatic posttranslational modifications. Specifically, we advocate for site-specific incorporation of these modifications into target proteins using advanced chemical and molecular biology techniques.

Graphical abstract: Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases

Article information

Article type
Review Article
Submitted
16 Sep 2024
Accepted
18 Dec 2024
First published
19 Dec 2024
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2025,6, 129-149

Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases

T. Baldensperger, M. Preissler and C. F. W. Becker, RSC Chem. Biol., 2025, 6, 129 DOI: 10.1039/D4CB00221K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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