Proteasome Dysregulation in Parkinson’s Disease: Insights from Blood-Based Analyses

: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. The peripheral biomarkers that reflect these cellular perturbations remain incompletely defined. This study aimed to evaluate the enzymatic activity and gene expression of two key protein degradation enzymes, Acyl PEptide Hydrolase (APEH) and Proteasome Subunit Beta Type-5 (PSMB5), in the peripheral blood of PD patients and to relate these findings to the severity of the disease. Thirteen PD patients and 13 age-matched healthy controls (HLT) were recruited. APEH and PSMB5 chymotrypsin-like (CT-like) activity were measured in whole blood, erythrocytes and immune cell fractions. Gene expression analysis was performed for APEH and PSMB5 and their related genes, plus other genes typical of parkinsonism or indicative of metabolic alterations: N(alpha)-acetyltransferase (NAA10) Aminoacylase 1 (ACY1), Ubiquitin-activating enzyme 1 (UBA1), Ubiquitin conjugating enzyme E2 I (UBE2I), Parkin RBR E3 ubiquitin protein ligase (PRKN), Alpha-synuclein (SNCA), Parkinsonism associated deglycase DJ-1 (PARK7), and mitochondrial Mn-SOD (SOD2). APEH activity did not differ significantly between PD and HLT in whole blood cells or cellular fractions. Conversely, PSMB5 CT-like activity was reduced in lymphocytes from PD patients, whereas erythrocytes and whole blood exhibited elevated activity. No changes in APEH and PSMB5 expression were observed, while PARK7 significantly decreased in patients with PD. Correlation analysis showed that proteasomal changes correlated with disease severity, and cognitive impairment. Our findings revealed compartment-specific proteasomal dysregulation in the peripheral blood of PD patients, suggesting systemic proteostasis imbalance. These alterations appeared more pronounced in patients with more severe clinical progression. This study supports the potential of peripheral proteasomal activity profiles as biomarkers linked to PD progression, warranting further investigation in larger cohorts.