Post-Translational Modifications in Disease Research

Proteins are the main executors of life activities, but they do not remain "unchanged" after synthesis. At different stages following synthesis, proteins undergo post-translational modifications (PTMs) to acquire new functions. These modifications act like "molecular tags" that determine where a protein functions, with whom it interacts, and whether it will be activated or degraded. PTMs are essential for maintaining normal physiological functions, and once dysregulated, they often trigger diseases. For instance, phosphorylation can act like a molecular "switch" to turn signaling pathways on or off; acetylation regulates gene expression; and ubiquitination determines whether certain proteins are degraded or retained. When the balance of these modifications is disrupted, cellular function is severely impaired, ultimately leading to diseases such as cancer, neurodegenerative disorders, or immune dysfunction.

 

Figure 1. Biological Functions and Disease Relationships of PTMs

 

Association Between PTMs and Diseases

1. Alzheimer's Disease

The main pathological features of Alzheimer’s disease include amyloid-β plaques and tau protein tangles, with PTMs playing a decisive role in this process. Hyperphosphorylated tau loses its ability to stabilize microtubules and forms neurofibrillary tangles that are toxic to neurons. At the same time, defects in the ubiquitination process prevent misfolded proteins from being cleared, further aggravating abnormal protein accumulation. These aberrant modifications together drive neuronal damage and cognitive decline.

 

2. Cancer

One of the most common molecular features of cancer is the persistent activation of signaling pathways, and PTMs are key drivers of this phenomenon. Pathways such as EGFR and MAPK are often locked in an "on" state due to aberrant phosphorylation, causing uncontrolled cell growth and proliferation. Meanwhile, imbalances between histone acetylation and deacetylation alter chromatin structure, leading to silencing of tumor suppressor genes and abnormal activation of oncogenes. These findings highlight the dual role of PTMs in tumorigenesis and explain why kinase inhibitors and histone deacetylase inhibitors have become critical agents in precision oncology.

 

3. Diabetes

PTMs also play important roles in diabetes and its complications. Chronic hyperglycemia induces non-enzymatic glycation of proteins, producing advanced glycation end-products (AGEs) that damage vascular endothelium and neurons, contributing to diabetic complications. In addition, abnormal acylation disrupts the normal function of insulin receptors and metabolic enzymes, impairing insulin signaling and leading to insulin resistance. Thus, PTMs are not only involved in the pathogenesis of diabetes but also serve as potential biomarkers for disease prediction and clinical management.

 

4. Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disease closely linked to aberrant PTMs. Patients often exhibit excessive citrullination, which alters the antigenicity of self-proteins and causes the immune system to misidentify them as foreign, triggering autoimmune attacks. Moreover, elevated carbonylation and nitration levels increase oxidative stress in joint tissues, promote inflammatory factor release, and exacerbate joint damage and disease progression.

 

5. Parkinson's Disease

The pathological hallmark of Parkinson’s disease is the aggregation of α-synuclein into Lewy bodies, and PTM dysregulation is a major driving force. Defects in ubiquitination and SUMOylation reduce the clearance efficiency of misfolded α-synuclein, leading to its accumulation within neurons. Meanwhile, abnormal phosphorylation accelerates aggregation and impairs mitochondrial function, resulting in energy metabolism disorders and neuronal apoptosis. PTMs are therefore crucial to understanding the pathogenesis of Parkinson’s disease.

Clinical Value and Application Prospects

1. Early Diagnosis: Specific modification patterns, such as hyperphosphorylation of tau protein in Alzheimer’s disease, can serve as biomarkers in blood or cerebrospinal fluid for early disease detection.

 

2. Prognosis Assessment: PTM levels are closely associated with disease progression. For example, the accumulation of AGEs predicts the risk of diabetic complications, while citrullinated proteins correlate with inflammation activity in rheumatoid arthritis.

 

3. Drug Development: Enzymes that regulate PTMs provide abundant drug targets. Kinase inhibitors and histone deacetylase inhibitors are already widely used in oncology, while modulators of ubiquitination and SUMOylation are emerging as promising drug candidates.

 

4. Precision Medicine: By profiling patient-specific PTM signatures, clinicians can identify disease subtypes and tailor personalized treatment strategies, thereby improving therapeutic accuracy and efficacy.

 

The value of PTMs in disease research is continuously expanding, with potential not only in elucidating molecular mechanisms but also in advancing clinical diagnostics and therapeutic translation. MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider, offers advanced proteomics, metabolomics, and biopharmaceutical analysis solutions to researchers in biochemistry, biotechnology, and biopharmaceutical fields. With extensive expertise and state-of-the-art platforms, MtoZ Biolabs is committed to helping global researchers and drug development teams explore the links between PTMs and diseases, accelerating the translation of scientific discoveries into clinical applications. For more details or customized solutions, please feel free to contact us.