Parkinson's disease (PD) is a disabling neurodegenerative disorder, causing both motor (bradykinesia, rigidity, rest tremor), and non-motor (depression, anxiety, cognitive impairment) symptoms, in the affected population. The pathological hallmarks of PD are the progressive degeneration of dopamine producing neurons of the substantia nigra pars compacta (SNc), and the presence of protein aggregates termed Lewy bodies. Although the etiological trigger causing the neurodegenerative process is currently unknown, various pathogenic pathways are believed to contribute to nigral cell death, including oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and proteasomal impairment. Modeling PD in animals is paramount for the development of new pharmacological targets for this disorder. In this study we report the development and characterization of a novel model of PD based on the intranigral infusion of the proteasomal inhibitor lactacystin in mice. This approach is based on current evidence indicating decreased proteasomal activity in the SNc of PD patients, as well as on previous literature findings indicating a similar approach for modeling PD in rats. Intranigral administration of lactacystin (3ug) to the left SNc of mice led to acute and non-progressive damage to the nigrostriatal dopaminergic pathway, as evidenced by nigral TH immunohistochemistry and evaluation of striatal dopamine content at 1w and 3w post surgery. Loss of striatal DA content induced parkinsonian motor features, characterized by impaired motor coordination and balance, forelimb akinesia, and sensorimotor neglect. Furthermore, behavioral analysis of lactacystin treated mice also indicated the development of non-motor features, such as increased anxiety and perseverative behavior, relevant for the symptomatology of PD. In conclusion, we developed a novel approach for modeling PD in mice by stereotaxic administration of lactacystin to the left SNc. Preliminary application of this model on system xc- deficient mice demonstrates its applicability for neuroprotective trials, and indicates that system xc-, a cystine-glutamate antiporter, might be a novel therapeutic target for this disorder.
Original languageEnglish
Title of host publicationCenter for Neurosciences PhD Day, Brussels, Belgium 2014
Publication statusPublished - 13 Mar 2014
EventPhD day Center for Neurosciences - Faculty of Medicine, Vrije Universiteit Brussel., Brussels, Belgium
Duration: 13 Mar 201413 Mar 2014

Seminar

SeminarPhD day Center for Neurosciences
CountryBelgium
CityBrussels
Period13/03/1413/03/14

    Research areas

  • Parkinson's disease, lactacystin, mouse model

ID: 2510881