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Research article
Zaijun Zhang
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Background: The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of these processes has been implicated in the pathogenesis of Parkinson’s disease (PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein (α-syn) clearance and attenuate degeneration of nigral dopaminergic neurons in PD. Methods: Neurotoxin-induced in vitro PD model, 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice model, unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA)-lesioned rat model, and transgenic mice overexpression of human A53T mutant α-synuclein were used to evaluate the neuroprotective and neurorescue effect of tetramethylpyrazine nitrone (TBN), a free radical scavenger, and its regulation on PGC-1α/Nrf2 pathway. Results: TBN protected against 1-methyl-4-phenylpyridinium (MPP + ) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in cell models overexpressing the human A53T mutant α-syn. In MPTP-treated mice, unilateral 6-OHDA-lesioned rats, and the α-syn transgenic mice model, TBN improved motor impairment, increased survival of nigral dopaminergic neurons, and elevated striatal dopamine levels while decreasing the products of oxidative damage. Importantly, TBN down-regulated the α-syn level in the brain and serum of α-syn-transgenic mice. These in vitro and in vivo improvements were associated with activation of the PGC-1α/Nrf2 signaling pathway, resulting in reduced oxidative stress, and enhanced mitochondrial functions. Conclusions: Our work demonstrates that TBN activates PGC-1α/Nrf2 and increases the survival of nigral dopaminergic neurons. These results suggest that TBN warrants further development as a potential new PD treatment.
Keywords
Parkinson’s disease, tetramethylpyrazine nitrone, peroxisome proliferator-activated receptor γ co-activator 1α, Nuclear factor erythroid-2-related factor 2, α-synuclein
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research article
Zaijun Zhang
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 10 Jun, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular & Molecular Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of these processes has been implicated in the pathogenesis of Parkinson’s disease (PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein (α-syn) clearance and attenuate degeneration of nigral dopaminergic neurons in PD. Methods: Neurotoxin-induced in vitro PD model, 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice model, unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA)-lesioned rat model, and transgenic mice overexpression of human A53T mutant α-synuclein were used to evaluate the neuroprotective and neurorescue effect of tetramethylpyrazine nitrone (TBN), a free radical scavenger, and its regulation on PGC-1α/Nrf2 pathway. Results: TBN protected against 1-methyl-4-phenylpyridinium (MPP + ) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in cell models overexpressing the human A53T mutant α-syn. In MPTP-treated mice, unilateral 6-OHDA-lesioned rats, and the α-syn transgenic mice model, TBN improved motor impairment, increased survival of nigral dopaminergic neurons, and elevated striatal dopamine levels while decreasing the products of oxidative damage. Importantly, TBN down-regulated the α-syn level in the brain and serum of α-syn-transgenic mice. These in vitro and in vivo improvements were associated with activation of the PGC-1α/Nrf2 signaling pathway, resulting in reduced oxidative stress, and enhanced mitochondrial functions. Conclusions: Our work demonstrates that TBN activates PGC-1α/Nrf2 and increases the survival of nigral dopaminergic neurons. These results suggest that TBN warrants further development as a potential new PD treatment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
The full text of this article is available to read as a PDF.
This is a list of supplementary files associated with this preprint. Click to download.
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