Proteasome Inhibitors

The Parkinson's-Reversing Breakthrough

Cure for Parkinsons

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An important regulatory system within cells is the ubiquitin proteasome system (UPS), a large enzymatic complex involved in detoxification and degradation of ubiquitin-tagged proteins (125,126). Inhibition of the UPS can lead to the inability to remove toxic protein moieties, accumulation of protein aggregates, neuronal dysfunction, and cell death (127,128). The identification of genes involved in familial forms of parkinsonism, especially parkin (an E3 ligase of UPS) and UCH-L1 (ubiq-uitin carboxy terminal hydrolase L1), have implicated a role of the UPS in PD (127-130). Therefore, targeting the UPS through elevated oxidative stress, introduction of various gene mutants, or pharmacological targeting have been tested for developing parkinsonian features in animal models. The infusion of inhibitors of the UPS such as lactacystin and epoxymycin to the basal ganglia has been reported to result in the loss of tyrosine hydroxylase and DAT immunoreactivity, dopamine depletion, and the occurrence of protein inclusions in midbrain dopaminergic neurons spared from cell death (131,132). The potential impact of using proteasome inhibitors to generate models of PD is in its early phase where the reproducibility of different regimens is being evaluated, including differences in species (rats vs. mice) and strain susceptibility, efficacy of different chemical agents, and mode of delivery.

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