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 -synuclein (-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by -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 -syn with the familial-PD linked mutation A30P, DJ-1 silencing increased -syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of -syn (TAT-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-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 -syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.
| Original language | English |
|---|---|
| Pages (from-to) | 13-23 |
| Number of pages | 11 |
| Journal | Neurodegenerative Diseases |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Mar 6 2015 |
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Keywords
- -Synuclein
- 6-Hydroxydopamine
- DJ-1 protein
- Parkinson's disease
- Therapy
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
- Medicine(all)
Cite this
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; Albani, Diego.
In: Neurodegenerative Diseases, Vol. 15, No. 1, 06.03.2015, p. 13-23.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The parkinson's disease-related protein dj-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity
AU - Batelli, Sara
AU - Invernizzi, Roberto William
AU - Negro, Alessandro
AU - Calcagno, Eleonora
AU - Rodilossi, Serena
AU - Forloni, Gianluigi
AU - Albani, Diego
PY - 2015/3/6
Y1 - 2015/3/6
N2 - 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 -synuclein (-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by -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 -syn with the familial-PD linked mutation A30P, DJ-1 silencing increased -syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of -syn (TAT-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-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 -syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.
AB - 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 -synuclein (-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by -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 -syn with the familial-PD linked mutation A30P, DJ-1 silencing increased -syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of -syn (TAT-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-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 -syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.
KW - -Synuclein
KW - 6-Hydroxydopamine
KW - DJ-1 protein
KW - Parkinson's disease
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=84924269795&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924269795&partnerID=8YFLogxK
U2 - 10.1159/000367993
DO - 10.1159/000367993
M3 - Article
VL - 15
SP - 13
EP - 23
JO - Neurodegenerative Diseases
JF - Neurodegenerative Diseases
SN - 1660-2854
IS - 1
ER -