The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity

Batelli, Sara; Invernizzi, Roberto William; Negro, Alessandro; Calcagno, Eleonora; Rodilossi, Serena; Forloni, Gianluigi und Albani, Diego (2015): The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity. In: Neuro-degenerative diseases, Bd. 15, Nr. 1: S. 13-23

Abstract

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 \textgreeka-synuclein (\textgreeka-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by \textgreeka-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 \textgreek{a}-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased \textgreek{a}-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of \textgreek{a}-syn (TAT-\textgreek{a}-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-\textgreek{a}-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 \textgreek{a}-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.

• Dokumententyp: Zeitschriftenartikel
• Publikationsform: Publisher's Version
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Allianz-/Nationallizenz: Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
• Sprache: Englisch