Abstract
Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturbances. Various pathogenic pathways drive disease progression including oxidative stress, mitochondrial dysfunction, α-synuclein aggregation and impairment of protein degradation systems. Dysfunction of the ubiquitin-proteasome system in the substantia nigra of Parkinson's disease patients is believed to be one of the causes of protein aggregation and cell death associated with this disorder. Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration. Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder. In order to further describe the proteasome inhibition model of Parkinson's disease, we characterized the unilateral lactacystin model, performed by stereotaxic injection of the toxin in the substantia nigra of mice. We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms. We report that unilateral administration of 3 μg lactacystin to the substantia nigra of mice leads to partial (~40%) dopaminergic cell loss and concurrent striatal dopamine depletion, accompanied by increased expression of Ser129-phosphorylated α-synuclein. Behavioral characterization of the model revealed parkinsonian motor impairment, as well as signs of non-motor disturbances resembling early stage Parkinson's disease including sensitive and somatosensory deficits, anxiety-like behavior, and perseverative behavior. The consistent finding of good face validity, together with relevant construct validity, warrant a further evaluation of proteasome inhibition models of Parkinson's disease in pre-clinical research and validation of therapeutic targets.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting 1% of the world-wide population (Massano and Bhatia, 2012)
Immunodetection of α-Synuclein and S129-P α-Synuclein Mice in which we investigated the effect of LAC administration on α-synuclein and S129-P α-synuclein were sacrificed by an overdose of pentobarbital (Nembutal, Ceva Sante Animale, Brussels Belgium), and transcardially perfused with NaCl 0.9% for 3 min, followed by freshly depolymerized 4% paraformaldehyde in NaCl 0.9% supplemented with 0.85% H3PO4 for an additional 6 min
Failure to achieve clinical translation might stem from various reasons, but it has been hypothesized that one could be the limited diversity of animal models used (Jenner, 2008; Duty and Jenner, 2011; Dexter and Jenner, 2013)
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting 1% of the world-wide population (Massano and Bhatia, 2012). The main symptoms of PD are motor-related, with the cardinal features of bradykinesia, motor rigidity, and rest tremor forming the basis of the neurological classification of this disorder These typical motor disturbances are believed to be the manifestation of degeneration of dopamine (DA) producing neurons of the Substantia Nigra (SN) pars compacta (SNc) that project to the striatum. Significant effort has been invested in developing strategies to stop disease progression, the current management of PD still relies on symptomatic treatment with DA replacement strategies. These approaches can be beneficial in the first years after diagnosis, the relentlessly progressive nature of PD makes them less efficient in controlling the disease, and can be the cause of disabling drug-induced side-effects (Schapira, 2009). The failure to achieve neuroprotection in PD can stem from various causes, one explanation for the inability to successfully translate positive pre-clinical findings could be the limited diversity of animal models used (Jenner, 2008)
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