Dataset Information

Targeting Mitochondrial Complex I Deficiency in MPP⁺/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

ABSTRACT:

Background

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP⁺ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP⁺-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice.

Results

The study in vitro showed NDI1 prevented MPP⁺-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra.

Conclusions

NDI1 compensates for the defective complex I in MPP⁺/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance.

SUBMITTER: Li H

PROVIDER: S-EPMC11003148 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

Targeting Mitochondrial Complex I Deficiency in MPP<sup>+</sup>/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Li Hongzhi H Zhang Jing J Shen Yuqi Y Ye Yifan Y Jiang Qingyou Q Chen Lan L Sun Bohao B Chen Zhuo Z Shen Luxi L Fang Hezhi H Yang Jifeng J Gu Haihua H

Biological procedures online 20240409 1

<h4>Background</h4>MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP<sup>+</sup> by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP<sup>+</sup>-treated SH-SY5Y cells and ...[more]

PMID: 38594619

Similar Datasets

Project description:Despite much efforts in the last few decades, the mechanism of degeneration of dopamine (DA) neurons in the substantia nigra (SN) in Parkinson's disease (PD) remains unclear. This represents a major knowledge gap in idiopathic and genetic forms of PD. Among various possible key factors postulated, iron metabolism has been widely suggested to be involved with fueling oxidative stress, a known factor in the pathogenesis of PD. However, the correlation between iron and DA neuron loss, specifically in the SN, has not been described in experimental animal models with great detail, with most studies utilizing rodents and, rarely, non-human primates. In the present study, aiming to gain further evidence of a pathological role of iron in PD, we have examined the correlation of iron with DA neuron loss in a non-human primate model of PD induced by MPTP. We report a significant iron accumulation accompanied by both DA degeneration in the SN and motor deficits in the monkey that displayed the most severe PD pathology and behavioral deficits. The other two monkeys subjected to MPTP displayed less severe PD pathologies and motor deficits, however, their SN iron levels were significantly lower than controls. These findings suggest that high iron may indicate and contribute to heightened MPP+-induced PD pathology in late or severe stages of PD, while depressed levels of iron may signal an early stage of disease. Similarly, using a cell culture preparation, we have found that high doses of ferric ammonium citrate (FAC), a factor known to enhance iron accumulation, increased MPP+-induced cell death in U251 and SH-SY5Y cells, and even in control cells. However, at low dose FAC restored or increased the viability of U251 and SH-SY5Y cells in the absence or presence of MPP+. These observations imply that high levels of iron likely contribute to or heighten MPP+ toxicity in the later stages of PD. While we report reduced iron levels in the earlier stages of MPTP induced PD, the significance of these changes remains to be determined.

Dataset Information

Targeting Mitochondrial Complex I Deficiency in MPP⁺/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Background

Results

Conclusions

Publications

Targeting Mitochondrial Complex I Deficiency in MPP<sup>+</sup>/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Background

Results

Conclusions

Publications

Targeting Mitochondrial Complex I Deficiency in MPP<sup>+</sup>/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Targeting Mitochondrial Complex I Deficiency in MPP⁺/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.