System xc- as a potential therapeutic target for glutamate excitotoxicity and alpha-synuclein pathology in Parkinson’s disease

Eduard-Mihai Bentea, Mustafa Varcin, Sophie Sarre, Yvette Michotte, Ann Massie

Onderzoeksoutput: Meeting abstract (Book)

Samenvatting

Parkinson's disease (PD) is a neurodegenerative disorder with important motor manifestations, and can only be treated symptomatically. Aggregation of the alpha-synuclein (a-syn) protein is considered to be an important factor in PD pathogenesis (1). Also, excitotoxicity caused by increased glutamate levels in the environment of the neurons, is believed to contribute to the disease process (2). Increased glutamate levels have been observed in animal models of PD (3), and we have previously demonstrated dynamic changes in glutamate transporters that might underlie this dysregulated glutamate homeostasis (4-6). System xc- is a cystine/glutamate antiporter that imports cystine in the cytoplasm, and exports glutamate to the extracellular environment. Therefore, increased expression of this transporter may lead to excitotoxic damage (7). On the other hand, reduced activity might lead to glutathione depletion (due to cysteine shortage) and could thus aggravate pathology by reducing the antioxidant capacity of cells. We have previously shown that xCT, the specific subunit of system xc-, is upregulated in the striatum of a 6-hydroxydopamine (6-OHDA) rat model of PD (4). Moreover, we observed that system xc- deficient mice are highly protected against 6-OHDA-induced neurodegeneration (8). Since recent evidence indicated a potential cross-link between glutamate excitotoxicity and a-syn pathology (9,10), we will investigate the interactions between glutamate excitotoxicity, system xc-, and a-syn pathology, in a new model of PD that replicates impaired protein homeostasis via inhibition of the ubiquitin proteasome system. In this new model, lactacystin (LAC), a selective proteasome inhibitor, is administered to the substantia nigra pars compacta (SNc) of adult mice, by stereotaxic microinjection. We are validating the model by investigating classical PD pathology markers, such as dopamine depletion in the striatum (using HPLC), dopaminergic neurodegeneration in the SNc (using immunohistochemistry and Western blotting), as well as motor impairment (using rotarod, open-field, and cylinder tests). Next, we will investigate a-syn pathology markers, such as a-syn accumulation, modification (oxidation/nitration), and oligomerization in the midbrain, using Western blotting. Also, we will assay the levels of a-syn oligomers in the frontal cortex, as a sign of pathology spread within the brain. After validating the model, we will continue our focus on system xc- and investigate whether the transporter is also upregulated in the LAC model. Next, we will administer LAC to system xc- deficient mice. By doing so, we hope to confirm our initial neuroprotective effect observed in 6-OHDA treated mice (8) in another model of PD that also replicates a-syn pathology. Finally, we will administer a selective system xc- inhibitor to LAC treated mice as a potential pharmacological intervention. The results of our research will reveal whether system xc- is an important factor in PD pathogenesis, and also whether inhibition of system xc- might be a therapeutic strategy for PD.

REFERENCES: (1) Schulman et al. Annu Rev Pathol 6:193-222 (2011) (2) Caudle et al. Exp Neurol 220:230-3 (2009) (3) Meshul et al. Neuroscience 88: 1-16 (1999) (4) Massie et al. Neuroreport 19:1589-92 (2008) (5) Massie et al. Neurochem Int 57:572-8 (2010) (6) Massie et al. Neurochem Int 57:111-8 (2010) (7) Bridges et al. Br J Pharmacol 165:20-34 (2012) (8) Massie et al. FASEB J 25: 1359-69 (2011) (9) Cheng et al. J Neurochem 119:815-825 (2011) (10) Huls et al. J Neurochem 117: 868-878 (2011)
Originele taal-2English
Titel16th Forum of Pharmaceutical Sciences, Blankenberge
StatusPublished - 8 mei 2012

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