Parkinson's disease (PD) is a neurodegenerative disorder clinically characterized by motor-related impairment which is 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. Accordingly, 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. It has been shown that local administration of the proteasomal inhibitor lactacystin (LAC) to the rodent nigrostriatal tract, induces nigrostriatal degeneration, as well as a-synuclein pathology both in rats and in mice (Xie et al. J Neurochem 2010 115(1):188-199; McNaught et al. Neuroreport 2002 13(11):1437-1441; Fornai et al. J Neurosci 2003 23(26):8955-8966). 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. Administering three microgram of LAC to the substantia nigra leads to acute and stable neurodegeneration of DA-ergic neurons and nerve terminals, as determined at 1w and 3w post lesion. This was accompanied by progressive motor behaviour impairment, and development of anxiety-like behaviour 3w post injection. 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 modulators of neurodegeneration, by generating the model on transgenic mice.
Original languageEnglish
Title of host publication43rd Annual Meeting of the Society for Neuroscience, 9-13 November 2013, San Diego, USA
Publication statusPublished - 9 Nov 2013
EventUnknown -
Duration: 9 Nov 2013 → …

Conference

ConferenceUnknown
Period9/11/13 → …

    Research areas

  • Parkinson's disease, proteasome, mouse model

ID: 2510088