Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Clinical manifestations of PD are motor-related and attributed to dopaminergic cell loss within the substantia nigra pars compacta (SNc), leading to striatal dopamine (DA) depletion. Various pathogenic pathways drive disease progression, including protein (a-synuclein) aggregation, oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and proteasomal impairment. Different animal models of PD have been developed that simulate one or more aspects of the human pathogenesis. However, most fail to reproduce the accumulation and aggregation of a-synuclein, an event that is ubiquitous in the human pathology. Therefore, at the present moment, there is an important need for animal models that reproduce a-synuclein pathology in a manner that is relevant for sporadic PD. A recent approach in this direction involves the local administration of the proteasomal inhibitor lactacystin (LAC) to the rodent nigrostriatal tract, inducing nigrostriatal degeneration, as well as a-synuclein pathology both in rats and in mice. LAC mouse models of PD have been generated, however, only by local administration of the toxin to the medial forebrain bundle, leading to retrograde transport to the SNc, and possibly anterograde transport to the striatum. However, the proteasome activity has been found to be decreased in the SNc of PD patients, but not in the striatum. In order to develop a more specific model of proteasomal inhibition, we investigated the effect of the local administration of LAC to the SNc of mice. We administered different doses of LAC, and evaluated the integrity of the nigrostriatal tract, as well as the motor behaviour of the treated mice, at different time points. Our data show that nigral administration of LAC leads to a dose dependent decrease in motor function, as well as to a dose dependent degeneration of the nigrostriatal tract, both at the level of the SNc, and at the level of the striatum. Therefore, we found that nigral proteasomal inhibition can model PD in mice both at the cellular and behavioural level. Further investigation will reveal additional features of the model, including the level of a-synuclein pathology, as well as the involvement of other pathogenic pathways, such as glutamate excitotoxicity. Developing this model in mice will also allow us to further investigate different genetic modulators of neurodegeneration, by generating the model on transgenic mice.
|Tijdschrift||Journal of Neurochemistry|
|Nummer van het tijdschrift||s1|
|Status||Published - 2013|
|Evenement||The 24th Biennial Meeting of the International Society for Neurochemistry and the American Society for Neurochemistry - Cancun, Mexico|
Duur: 20 apr 2013 → 24 apr 2013