The proteasome inhibition mouse model of Parkinson's disease: insights into molecular and behavioral changes following intranigral lactacystin injection

In Parkinson's disease (PD), the progressive degeneration of the nigrostriatal dopamine (DA) pathway leads to loss of striatal DA content, dysregulation of the basal ganglia motor circuit, and inhibition of movement. In addition, PD patients present with non-motor symptoms that can be debilitating in terms of impact on quality of life. From a molecular perspective, various factors have been implicated in the loss of DA neurons in PD, including failure of protein degradation pathways leading to aberrant protein accumulation. The aim of the current study was to evaluate molecular and behavioral abnormalities in a mouse model of PD, based on the intranigral infusion of proteasome inhibitor lactacystin (LAC). C57BL/6J mice, 12 weeks of age, were stereotaxically injected with 3 µg LAC or saline in the left substantia nigra pars compacta. One or three weeks following surgery, mice were tested in various behavioral paradigms, and brain tissue further processed for evaluating molecular and neurodegenerative changes. Our findings demonstrate that LAC-treated mice show loss of nigral DA-ergic neurons and concurrent striatal DA depletion, and develop behavioral (motor and non-motor) deficits, including impaired motor coordination and balance, motor asymmetry, hyperactivity, anxiety-like behavior, somatosensory dysfunction, and response perseveration. Furthermore, LAC infusion led to accumulation of Ser129-phosphorylated α-synuclein and increased VGLUT2 immunoreactivity in the ipsilateral substantia nigra. Our findings indicate that mice treated with proteasome inhibitor LAC develop parkinsonian features, including motor and non-motor impairment, pathological α-synuclein accumulation, and glutamatergic dysfunction that could be linked with increased activity of the subthalamic nucleus.