Abstract
BACKGROUND: The ubiquitin-proteasome system (UPS) is crucial for maintaining cellular homeostasis through protein degradation. Its dysfunction has been implicated in various neurodegenerative diseases, but a comprehensive quantitative proteomic analysis of UPS components in early-onset forms remains limited. OBJECTIVE: This study aimed to quantitatively profile the proteome of key UPS components in brain tissue from individuals with early-onset neurodegenerative diseases (EON) compared to age-matched controls. METHODS: Quantitative proteomic analysis using mass spectrometry-based techniques was performed on prefrontal cortex tissue samples from EON patients (n=10) and healthy controls (n=10). Differential expression analysis focused on proteins involved in ubiquitination, proteasomal subunits, deubiquitinating enzymes, and their associated regulatory factors. Pathway enrichment analysis and protein-protein interaction networks were constructed to identify dysregulated pathways. RESULTS: Our proteomic analysis identified significant alterations in several UPS components in EON brain tissue. Notably, we observed a consistent upregulation of E3 ubiquitin ligases implicated in protein aggregation, alongside a downregulation of specific proteasomal subunits. Deubiquitinating enzyme activity also appeared to be altered, suggesting a complex regulatory imbalance. Pathway analysis highlighted the enrichment of pathways related to protein folding, endoplasmic reticulum stress, and inflammatory responses, all interconnected with UPS function. [[FIGURE: Volcano plot showing differentially expressed UPS proteins between EON patients and controls]]. CONCLUSION: This study provides the first quantitative proteomic evidence of widespread UPS dysregulation in early-onset neurodegenerative diseases. The observed imbalances in ubiquitination and proteasomal degradation machinery, coupled with associated cellular stress pathways, underscore the critical role of UPS integrity in neuronal health and suggest potential therapeutic targets for intervention in these devastating conditions.