Parkinson's disease (PD) is a neurodegenerative disorder with important motor manifestations, that currently can only be treated symptomatically. Aggregation of the a-synuclein protein is considered to be an important factor in PD pathogenesis. Also, inhibition of the proteasome system, as well as glutamate excitotoxicity are believed to contribute to the disease process. However, potential interactions between these pathogenic pathways are currently unknown. System xc- is a plasma membrane antiporter that imports cystine, and exports glutamate to the extracellular environment. We have previously shown that xCT, the specific subunit of system xc-, is upregulated in the striatum of the 6-hydroxydopamine rat model of PD, constituting a potential source of glutamate excitotoxicty. Moreover, we observed that xCT knock-out mice are highly protected against 6-hydroxydopamine-induced neurodegeneration. We recently investigated the contribution of system xc- to neurodegeneration in an additional model of PD, based on the local administration of lactacystin, a proteasomal inhibitor, to the substantia nigra. Consistent with previous findings, we observed that xCT knock-out mice are protected against lactacystin-induced neurodegeneration, and show improved motor behavior compared to wild-type littermates. These findings confirm that targeting system xc- might represent an innovative pharmacological intervention in PD. Furthermore, as lactacystin models exhibit a-synuclein pathology, we will further investigate the potential involvement of reduced a-synuclein aggregation to the observed neuroprotective effects. This will allow us to establish potential links between a-synuclein aggregation, glutamate excititoxicity, and proteasomal impairment, all of which are involved in the pathogenesis of PD, as basis for novel neuroprotective interventions.
Original languageEnglish
Title of host publication10th Bi-annual Scientific Meeting of the Belgian Society of Neuroscience, 31 May 2013 Brussels
Publication statusPublished - 31 May 2013

    Research areas

  • Parkinson's disease, glutamate, pharmacology, lactacystin

ID: 2356972