Blood cell mitochondrial dysfunction as early indicator of alpha-synuclein pathology in rats

Abstract Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein (α-syn)-containing inclusions. Although the precise mechanisms underlying this process remain incompletely understood, mitochondrial dysfunction is a critical factor in disease pathogenesis. PD is typically diagnosed after substantial neurodegeneration has occurred, when available therapies remain symptomatic and disease-modifying treatments are lacking. This underscores an urgent need for biomarkers that detect PD during its prodromal stages, prior to overt motor symptoms. In this study, we developed an early-stage rat model of PD via viral vector-induced overexpression of human α-syn in the SNpc and investigated whether peripheral mitochondrial alterations reflect early central pathology at 1 and 3 months after vector injection. We evaluated motor and non-motor behaviour, dopaminergic cell loss, brain expression of α-syn and peripheral cytokine levels. Brain tissue and blood cells were collected, and activities of mitochondrial electron transport chain complex activities were quantified using custom-made microarray-based assays. Overexpression of α-syn induced mild dopaminergic degeneration in absence of motor impairment and was associated with anxiety-like behaviour, consistent with prodromal PD. Systemic inflammatory markers were unchanged; however, mitochondrial activity in brain and peripheral blood cells showed significant alterations. Complex I activity was significantly reduced in both SNpc and platelets, showing a non-significant trend in peripheral blood mononuclear cells (PBMCs). In contrast, complex IV activity increased in platelets but decreased in PBMCs. Activities of the remaining complexes were unaffected. A logistic regression model based on complex I and IV activities accurately discriminated α-syn-overexpressing animals from controls. These findings demonstrate that peripheral mitochondrial electron transport chain dysfunction mirrors early α-syn-induced brain pathology and identifies blood-based mitochondrial profiling as a promising non-invasive strategy for early PD detection.