INTRODUCTION: Parkinson’s disease (PD) is primarily characterized by clinical symptoms such as muscle rigidity, tremor and bradykinesia, resulting from the irreversible degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). α-Synuclein aggregation in DA neurons plays a key role in PD pathogenesis, ultimately leading to neuronal death. Whilst animal models based on intracerebral administration of α-Synuclein fibrils into the nigrostriatal pathway faithfully reproduce early stages of PD, they do not induce DA neuron loss fast enough to generate robust motor deficits. In contrast, intranigral administration of the ubiquitin–proteasome system inhibitor lactacystin causes rapid dopaminergic neurodegeneration and motor symptoms, yet fails to reliably reproduce α -Synuclein aggregation typical of human PD.

AIM(S): The aim of this study was to develop a novel PD model combining intranigral administration of α-Synuclein fibrils with a low dose of lactacystin, thereby more closely resembling human PD pathology.

METHOD(S): Stereotactic unilateral administration of vehicle (2 µl PBS), lactacystin (0.5 µg), α-Synuclein fibrils (8 µg), or a combination of lactacystin and α-Synuclein fibrils into the SN was performed in male Wistar rats, which were subsequently subjected to a series of non-invasive behavioral tests assessing forelimb use asymmetry, including the cylinder test, forelimb stepping test, and vibrissae-evoked forelimb placing test.

RESULTS: Vehicle-, lactacystin-, and α-Synuclein fibril-treated rats showed no significant forelimb asymmetry at 2 and 4 weeks post-surgery, whilst in contrast, the combined administration of lactacystin and α-Synuclein fibrils exhibited a significant reduction in use of the compromised forelimb across all tests.

CONCLUSIONS: This novel model induces significant motor deficits indicative of severe nigrostriatal impairment, offering a promising and efficient platform for studying PD mechanisms and evaluating therapeutic strategies.

FINANCIAL SUPPORT: This work was supported by the statutory funds of the Department of Brain Biochemistry, Maj Institute of Pharmacology, PAS.