The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity
| Autor: | Serena Rodilossi, Diego Albani, Sara Batelli, Roberto W. Invernizzi, Alessandro Negro, Gianluigi Forloni, Eleonora Calcagno |
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| Rok vydání: | 2014 |
| Předmět: |
Parkinson's disease
Protein Deglycase DJ-1 Pharmacology chemistry.chemical_compound Mice Downregulation and upregulation In vivo Mesencephalon Medicine Animals Oxidopamine Cells Cultured Alpha-synuclein Mice Knockout Oncogene Proteins Hydroxydopamine business.industry Dopaminergic Neurons Dopaminergic Parkinson Disease Peroxiredoxins medicine.disease Up-Regulation Mice Inbred C57BL Disease Models Animal Neurology chemistry Mutation Nerve Degeneration Synuclein alpha-Synuclein Neurology (clinical) business |
| Zdroj: | Neuro-degenerative diseases. 15(1) |
| ISSN: | 1660-2862 |
| Popis: | Background: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein α-synuclein (α-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by α-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA). Objective: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. Methods: We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration. Results: We found that in PC12/TetOn cells overexpressing α-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased α-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of α-syn (TAT-α-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-α-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain. Conclusion: DJ-1 appears to have a protective role against dopaminergic degeneration triggered by α-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD. |
| Databáze: | OpenAIRE |
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