Introduction

Neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of neuronal function and structure, often accompanied by the accumulation of misfolded protein aggregates. Parkinson’s disease, in particular, is marked by the presence of Lewy bodies and Lewy neurites, which are primarily composed of aggregated α-synuclein (α-syn) protein. The alpha-synuclein (α-syn) aggregates impair neuronal function and contributing to disease progression. Current treatments primarily target symptoms rather than disease modification.

A recent study published in Nature Communications by researchers from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and the Max Planck Institute of Psychiatry provides new insights into aspirin’s potential role in modulating protein degradation pathways. The study demonstrates that aspirin can impair proteasome activity through lysine acetylation while promoting lysosomal clearance of α-synuclein aggregates via K63-linked ubiquitination.

Aspirin, or acetylsalicylic acid, is a well-known nonsteroidal anti-inflammatory drug (NSAID) with a wide range of pharmacological effects, including anti-inflammatory, antiplatelet, and analgesic properties. Beyond its traditional uses, aspirin has been implicated in various health benefits, including cancer prevention and neuroprotection. This essay explores the potential application of aspirin in treating neurodegenerative diseases, with a focus on Parkinson’s disease, by examining its mechanisms of action, its effects on protein aggregation, and its therapeutic implications.

Aspirin’s Mechanisms of Action: Promotes K63-Linked Ubiquitination and Lysosomal Degradation

Aspirin is a potent acetylating agent that induces lysine acetylation on a wide range of cellular proteins. Lysine acetylation is a post-translational modification (PTM) that plays a crucial role in regulating protein function, stability, and interactions. Acetylation can alter protein conformation, affect enzymatic activity, and influence protein-protein interactions. In the context of neurodegenerative diseases, acetylation has been shown to modulate the aggregation and clearance of pathological proteins, such as α-synuclein in PD and tau in AD.

Ubiquitination, another key PTM, is essential for protein degradation via the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Ubiquitin chains can be linked through different lysine residues, with K48-linked ubiquitination typically targeting proteins for proteasomal degradation, while K63-linked ubiquitination is associated with lysosomal degradation and other cellular processes, such as DNA repair and signal transduction. The interplay between acetylation and ubiquitination is complex, as both modifications can occur on the same lysine residues, potentially competing for occupancy and influencing protein stability.

The study published in Nature Communications demonstrates that, using reversed-pulsed SILAC (rp-SILAC) proteomic analysis, aspirin impairs proteasome function without altering global protein abundance. Aspirin treatment led to a 48–63% reduction in proteolytic activity of the proteasome, confirming its inhibitory effect. Mass spectrometry data further revealed that aspirin induces acetylation of key proteasome subunits, including PSMB5, PSMB6, and PSMB7, which are essential for proteolysis. Thus, aspirin does not directly suppress lysine ubiquitination but instead impairs proteasome activity by acetylating proteasome subunits, thereby inhibiting proteasomal degradation. Interestingly, aspirin increases K63-linked ubiquitination, which promotes lysosomal degradation of protein aggregates. This dual mechanism of action, inhibiting proteasomal degradation while enhancing lysosomal clearance, suggests that aspirin could be a promising therapeutic agent for diseases characterized by protein aggregation, such as PD.

In Vitro Studies Show Aspirin Enhances α-Synuclein Clearance in Neurons

One of the hallmark features of Parkinson’s disease is the accumulation of α-synuclein aggregates, which are toxic to neurons and contribute to the progression of the disease. The clearance of these aggregates is crucial for maintaining neuronal health and function. The study by Gao et al. (2025) provides compelling evidence that aspirin promotes the clearance of α-synuclein aggregates through a K63 ubiquitination-dependent mechanism.

In cultured cells and primary neurons, aspirin treatment significantly reduced the levels of α-synuclein aggregates. This effect was dose-dependent, with higher concentrations of aspirin leading to more pronounced clearance of aggregates. Importantly, the clearance of α-synuclein aggregates was mediated by K63-linked ubiquitination, as demonstrated by experiments using mutant ubiquitin variants. Overexpression of K63R ubiquitin, which lacks the ability to form K63-linked chains, abolished the aspirin-induced clearance of α-synuclein aggregates, while wild-type and K48R ubiquitin did not. This finding highlights the critical role of K63 ubiquitination in the lysosomal degradation of α-synuclein aggregates.

Furthermore, the study showed that aspirin-induced K63 ubiquitination promotes the entry of α-synuclein aggregates into early endosomes, where they are subsequently degraded via the endosomal-lysosomal pathway. This mechanism is consistent with previous studies showing that K63-linked ubiquitination is involved in the sorting and degradation of protein aggregates by the autophagy-lysosome system. The ability of aspirin to enhance this pathway suggests that it could be a valuable therapeutic strategy for clearing toxic protein aggregates in neurodegenerative diseases.

In Vivo Studies Show Aspirin Improves Motor Function in a Parkinson’s Disease Mouse Model

To assess aspirin’s effects in vivo, researchers used a Parkinson’s disease (PD) mouse model in which α-synuclein preformed fibrils (PFFs) were bilaterally injected into the striatum, leading to PD-like symptoms, including locomotor impairments and dopaminergic (DA) neuronal loss. Aspirin was administered orally at 6 mg/kg/day for eight weeks, and behavioral improvements were monitored. The results revealed several significant findings. Aspirin treatment significantly improved motor function, particularly after eight weeks, as demonstrated by enhanced locomotion and coordination in rotarod and open field tests. Additionally, aspirin reduced phosphorylated α-synuclein (p-α-syn) aggregates in the striatum, as confirmed by immunohistochemical staining. Moreover, aspirin exhibited neuroprotective effects by preventing DA neuronal loss in the substantia nigra, despite the continued presence of synucleinopathy. Mass spectrometry analysis further demonstrated that aspirin-treated mice had increased K63-linked ubiquitination, consistent with in vitro findings. To establish that K63 ubiquitination mediates aspirin’s neuroprotective effects, researchers injected adeno-associated virus (AAV)-expressing WT, K48R, or K63R ubiquitin into the striatum of PD mice. Notably, mice expressing K63R ubiquitin did not exhibit behavioral improvements despite aspirin treatment, confirming that aspirin’s beneficial effects rely on K63-linked ubiquitination to facilitate α-syn clearance and neuroprotection.

Implications for Drug Development and Future Research

The findings from this study have significant implications for the development of new therapeutic strategies for Parkinson’s disease and other neurodegenerative disorders. Aspirin’s ability to modulate protein degradation pathways, particularly through K63-linked ubiquitination, offers a novel approach to targeting the underlying pathology of these diseases. By promoting the clearance of toxic protein aggregates, aspirin could potentially slow or halt the progression of neurodegeneration. However, several questions remain unanswered. For instance, the precise mechanisms by which aspirin increases K63-linked ubiquitination are not fully understood. It is possible that aspirin modulates the activity of key enzymes involved in ubiquitination, such as E3 ubiquitin ligases or deubiquitinases. Further research is needed to identify the specific molecular targets of aspirin and to elucidate the signaling pathways involved in its effects on ubiquitination.

Additionally, the optimal dosage and treatment duration for aspirin in the context of neurodegenerative diseases need to be determined. While the study by this study used relatively high concentrations of aspirin in cell culture experiments, the dosage used in the mouse model was consistent with clinical practice. Future studies should explore the dose-response relationship of aspirin in different models of neurodegeneration and assess its long-term safety and efficacy.

Conclusion

In conclusion, the study highlights the potential of aspirin as a therapeutic agent for neurodegenerative diseases, particularly Parkinson’s disease. By inhibiting proteasomal degradation and promoting K63-linked ubiquitination, aspirin enhances the clearance of toxic protein aggregates, such as α-synuclein, and protects neurons from degeneration. These findings open new avenues for drug development and provide a rationale for repurposing aspirin as a disease-modifying treatment for PD and other protein aggregation disorders. Further research is needed to fully understand the mechanisms underlying aspirin’s effects and to optimize its use in clinical settings. Nonetheless, the promise of aspirin as a neuroprotective agent offers hope for patients suffering from these devastating diseases.

Related Essay

Aspirin as a PROTAC and Molecular Glue Antagonist: A Hypothetical Consideration Based on Recent Findings

 

References

Gao, J., Liu, Y., Si, C., Guo, R., Hou, S., Liu, X., Long, H., Liu, D., Xu, D., Zhang, Z.-R., Liu, C., Shan, B., Turck, C. W., He, K., & Zhang, Y. (2025). Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination. Nature Communications, 16, 1438. https://doi.org/10.1038/s41467-025-56737-6.

Disclaimer: This information is intended solely for research purposes and does not serve as medical advice.

 

About Marin Biologic Laboratories (MarinBio)

Our Recent Publication/Meeting Presentation

American Society of Hematology (ASH) Annual Meeting 2024.

Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

Comprehensive Assay Solutions for In Vitro and Cell Based Potency Assays and Pharmacokinetics Studies- Our Expertise

With 30 years of expertise in cell culture, cell-based assays, and preclinical/clinical PK/PD analysis, we specialize in offering assay services essential for a wide variety of therapeutic drug development programs, preclinical studies, IND/BLA applications, and commercialization. Our comprehensive services include both preclinical non-GLP and GLP assays, as well as non-GMP and GMP assays, providing critical support throughout the entire development pipeline.

Watch the following video and explore our latest presentation on the development and validation of potency and pharmacokinetic (PK) assays for AAV vectors, highlighting innovative methodologies and industry-leading expertise.

 

 

Download the full presentation: Development of Custom Cell Based and In vitro Potency and Pharmacokinetics (PK) Assays for AAV vectors- Marin biologic Laboratories

Development of Cell-Based Potency Assays: Case Studies and Blogs from Marin Biologic Laboratories (MarinBio)

Drug Discovery & Development Assays Offered by Marin Biologic Laboratories (MarinBio)

Our Recent Blogs/Articles