Abstract
Drugs currently used for treating Parkinson's disease patients provide symptomatic relief without altering the neurodegenerative process. Our aim was to examine the possibility of using DJ-1 (PARK7), as a novel therapeutic target for Parkinson's disease. We designed a short peptide, named ND-13. This peptide consists of a 13 amino acids segment of the DJ-1-protein attached to 7 amino acids derived from TAT, a cell penetrating protein. We examined the effects of ND-13 using in vitro and in vivo experimental models of Parkinson's disease. We demonstrated that ND-13 protects cultured cells against oxidative and neurotoxic insults, reduced reactive oxygen species accumulation, activated the protective erythroid-2 related factor 2 system and increased cell survival. ND-13 robustly attenuated dopaminergic system dysfunction and in improved the behavioral outcome in the 6-hydroxydopamine mouse model of Parkinson's disease, both in wild type and in DJ-1 knockout mice. Moreover, ND-13 restored dopamine content in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. These findings validate DJ-1 as a promising therapeutic target in Parkinson's disease and identify a novel peptide with clinical potential, which may be significant for a broader range of neurological diseases, possibly with an important impact for the neurosciences.
Highlights
Current treatments for Parkinson’s disease (PD) provide temporary relief of symptoms without altering the disease progression
The most promising peptide we analyzed is a short peptide composed of 13 amino-acids derived from DJ-1, attached to a 7 aminoacids sequence derived from TAT that served as the cell penetrating peptide (CPP) moiety
In order to verify that ND-13 penetrates the cells, PC-12 cells exposed to ND13, vehicle or the TAT-derived CPP alone were immunostained with antibodies against TAT
Summary
Current treatments for Parkinson’s disease (PD) provide temporary relief of symptoms without altering the disease progression. The development of disease modifying treatments requires profound understanding of the neurodegenerative mechanisms leading to disease progression. The authors have submitted several patent applications, some of which have already been granted. We confirm that the patents relating to materials pertinent to this article do not alter our adherence to all PLOS ONE policies on sharing data and materials, as detailed in the guide for authors.
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