Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease

Abstract

Impairment of the ubiquitin proteasome system (UPS) has been proposed to play an important role in the pathogenesis of Parkinson's disease (PD). Mice with UPS impairment in the nigra have been used for investigating mechanisms underlying neurodegeneration and for testing pre-clinical drugs to treat PD. However, the pathological, biochemical and behavioral features of UPS impairment animal model of PD have not been fully evaluated. For this purpose, we developed a UPS impairment model of nigral dopamine (DA) neuron degeneration by microinjection with proteasome inhibitors lactacystin, PSI or MG-132 into the medial forebrain bundle (iMFB) of C57BL/6 mice and then systematically examined the animal's locomotor activities, and various pathological and biochemical markers of PD. We found that lactacystin iMFB induced a sustained DA neuron degeneration, which can be reproduced by PSI iMFB and MG-132 iMFB. In the animal model, DA neuron degenerated preferentially in the substantia nigra, accompanied by profound inhibition of proteasomal activity, activation of caspase 3, elevated insoluble ubiquitin conjugates and α-synuclein positive inclusion-like granules, activated glia, and decreased motor activities. Thus, this model recapitulates many neuropathological and behavioral features of PD, rendering it likely suitable for studying the mechanisms of nigral DA neuron degeneration and for testing the potential anti-PD medications.