Effect on intracellular delivery of thioredoxin- 1 on a cell line model of Parkinson's disease

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Yeung, Albert
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Parkinson disease (PD) is the second most common neurodegenerative disease and is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Current treatments include the use of dopamine agonists; however these treatments are only effective in reducing the symptoms during the early stages of the disease. The brains of the PD patients show an increased level of oxidative stress that is associated with increased dopamine oxidation and high iron levels. Dopamine is oxidized to 6-OHDA and converts to 6OHDA-quinone which is highly reactive and can extract electrons from sulfhydryl groups on proteins. This will lead to changes in structure and function of proteins and activation of cell death mechanisms. To maintain the proteins in their reduced state, the cells are equipped with glutathione (GSH) and thioredoxin (Trx) systems. These systems provide a source of reducing protons that can be used for scavenging 6-OHDA-quinone and other oxidants and rescuing the oxidized proteins. New reports indicate that despite much lower concentration, Trx system is much more important than GSH in PD, although the Trx level is especially decreased in the PD brain. We hypothesize that Trx protein can be used as a novel therapy for treatment of PD. The presence of Blood-Brain-Barrier (BBB) is effectively inhibits protein delivery into the brain, however we have generated a cell-penetrating peptide to deliver Trx across the BBB and into the neurons. For this project we use a cellular model of PD, and will test if our novel Trx protein therapy approach will enhance neuronal survival. This approach can have important impact in our progressively aging population. i
Parkinson's Disease, 6-OHDA-quinone, cellular model, Trx protein