Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted microbubble destruction (UTMD)-mediated PD model that could generate the disease phenotype via αSNCA CNS gene delivery. The formation of neuronal aggregates was analyzed with immunostaining. To evaluate the DA cell loss, we used tyrosine hydroxylase immunostaining and HPLC analysis on DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This loss of DA was associated with a dose-dependent impairment in motor function, as assessed by the rotarod motor assessment. We demonstrate that UTMD-induced SNCA expression initiates αSNCA aggregation and results in a 50% loss of DA in SN. UTMD-related dose-dependent neuronal loss was identified, and it correlates with the degree of impairment of motor function. In comparison to chemical neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and conventional intracerebral (IC)-injected animal models of PD, the UTMD-mediated αSNCA-based mouse model offers the advantage of mimicking the rapid development of the PD phenotype. The PD models that we created using UTMD also prove valuable in assessing specific aspects of PD pathogenesis and can serve as a useful PD model for the development of new therapeutic strategies.