Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative condition
accompanied by disabling motor symptoms. Preventing or delaying the
onset of neuronal death in this disorder represents a pending and
unmet need. Although various neuroprotective targets have been
proposed in pre-clinical studies, none have been validated as yet in
patients. A novel therapeutic target recently proposed in PD is system
xc-, a membrane cystine/glutamate antiporter. System xc- is induced
in pathological conditions and in turn releases high levels of
extracellular glutamate, which can become neurotoxic past a certain
threshold, triggering ‘excitotoxicity’. In the context of the current
thesis, we evaluated system xc- as a possible target for
neuroprotection in two toxin-based models with distinct mechanisms of
action: the intranigral lactacystin mouse model (proteasome inhibition)
and the systemic MPTP mouse model (mitochondrial dysfunction). In
the first part of the thesis, we characterized the behavioral,
neurochemical, and neurodegenerative changes following lactacystin
administration in mice as a model of early stage PD. Subsequently,
using mutant mice with a genetic deletion of xCT (the specific subunit
of system xc-), we investigated the involvement of system xc- in
lactacystin- or MPTP-induced loss of nigral dopamine neurons. Our
results indicate that absence of system xc- provides age-related
neuroprotective effects against lactacystin administration (observed in
aged, but not adult mice), but does not influence the
neurodegenerative changes following MPTP administration in adult mice
(sensitivity of aged mice not investigated). Our findings confirm the
involvement of system xc- in PD-related neurodegenerative changes in
the ageing brain and support its further development as
neuroprotective target.
Date of Award26 May 2016
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
SupervisorAnn Massie (Promotor), Ilse Smolders (Co-promotor), Dimitri De Bundel (Jury), Jacques De Keyser (Jury), Mathieu Vinken (Jury), Jean-Marc Taymans (Jury) & Dieter Scheller (Jury)

Keywords

  • Parkinson’s disease

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