Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

Goloborshcheva, Valeria V; Kucheryanu, V. G.; Воронина, Н. А.; Teterina, E V; Ustyugov, A. A.; Morozov, Sergey G.

doi:10.3390/biomedicines10092278

Cited by 8 publications

(4 citation statements)

References 128 publications

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“…MPTP, via its active metabolite MPP+, affects the dopaminergic system in the brain, resulting in a deficiency of the dopamine neurotransmitter, which is required for proper movement and motor control [62]. Dopamine depletion can cause slower movement and impaired motor function in animals injected with MPTP [63,64].…”

Section: Notable Locomotor Impairments Following Mptp Administrationmentioning

confidence: 99%

Mitophagy: A Bridge Linking HMGB1 and Parkinson’s Disease Using Adult Zebrafish as a Model Organism

et al. 2023

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High-mobility group box 1 (HMGB1) has been implicated as a key player in two critical factors of Parkinson’s disease (PD): mitochondrial dysfunction and neuroinflammation. However, the specific role of HMGB1 in PD remains elusive. We investigated the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on mitochondrial dysfunction and HMGB1-associated inflammatory genes as well as locomotor activity in zebrafish, aiming to elucidate the role of HMGB1 in PD. Adult zebrafish received MPTP injections, and locomotor activity was measured at 24- and 48-h post-administration. Gene expression levels related to mitophagy (fis1, pink1, and park2) and HMGB1-mediated inflammation (hmgb1, tlr4, and nfkb) were quantified through RT-qPCR analysis. Following MPTP injection, the significant increase in transcript levels of fis1, pink1, and park2 indicated notable changes in PINK1/Parkin mitophagy, while the upregulation of hmgb1, tlr4, and nfkb genes pointed to the activation of the HMGB1/TLR4/NFκB inflammatory pathway. Furthermore, MPTP-injected zebrafish exhibited decreased locomotor activity, evident through reduced distance travelled, mean speed, and increased freezing durations. HMGB1 plays a major role in cellular processes as it is involved in both the mitophagy process and functions as a pro-inflammatory protein. MPTP administration in adult zebrafish activated mitophagy and inflammatory signaling, highlighting the significant role of HMGB1 as a mediator in both processes and further emphasizing its significant contribution to PD pathogenesis.

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Section: Notable Locomotor Impairments Following Mptp Administrationmentioning

confidence: 99%

Mitophagy: A Bridge Linking HMGB1 and Parkinson’s Disease Using Adult Zebrafish as a Model Organism

et al. 2023

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“…When it is metabolized in the body, it produces a compound called MPP+ (1-methyl-4-phenylpyridinium), which is highly toxic to DA neurons in the substantia nigra, a brain region affected in PD 19 . MPP+ is structurally similar to DA, and this structural resemblance allows it to be taken up by DA neurons via DAT, which are proteins that normally transport DA into these neurons 20 . Inside the dopaminergic neurons, MPP+ interferes with the function of mitochondrial Complex I, which is responsible for generating adenosine triphosphate (ATP), the cell’s primary energy source 21 .…”

Section: Introductionmentioning

confidence: 99%

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Treated Adult Zebrafish as a Model for Parkinson’s Disease

Bagwell,

Shin,

Henkel

et al. 2024

Preprint

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Dopamine (DA) is a neuroprotective catecholamine and neurotransmitter that works to regulate cognitive functions (Channer et al., 2023). Patients affected by Parkinson’s Disease (PD) experience a loss of dopaminergic neurons, lower levels of DA, and downregulated neural DA production. This leads to cognitive and physical decline that is the hallmark of PD. Currently, no cure exists for this prevalent neurodegenerative disease.Danio rerio, or zebrafish, have become an increasingly popular disease model used in PD pharmaceutical development. This model still requires extensive development to better characterize which PD features are adequately represented. Furthermore, the great majority of PD zebrafish models have been performed by treating embryos, which may not be relevant towards age-related human PD development. As an improvement, matureD. rerio(18 months) were treated with the neurotoxic prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through intraperitoneal injection to induce Parkinsonianism. Behavioral analysis confirmed the disparity in movement between saline-injected control and the MPTP experimental group, in which swim distance and speed were significantly lowered seven days after MPTP injection. Simultaneously, cognitive decline was apparent in MPTP zebrafish compared to control, demonstrated by decreased alternation in a y-maze. RT-qPCR confirmed trends consistent with downregulation in Parkinsonian genetic markers, specifically DA transporter (DAT), MAO-B, PINK1. In summary, mature zebrafish injected with MPTP present with similar movement and cognitive decline as compared to human disease. Despite its benefits, this model does not appear to recapitulate full pathophysiology of the disease with the full profile of expected gene downregulation. Because of this, it is important that researchers looking for pharmacological interventions for PD only use this zebrafish model when targeting the human-relevant PD symptoms and causes that are represented.

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“…MPTP in the brain is converted to toxic metabolite MPP+ by selectively inhibiting complex I of the mitochondrial electron transport chain. Mitochondrial dysfunction results in ATP disturbance, abnormal lipid and amino acid metabolism [ 10 ]. Anticholinergic drugs and other medications are used to treat PD.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

Atiq

Lee

Khan

et al. 2023

IJMS

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Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1β-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson’s disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25–30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration.

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Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

Cited by 8 publications

References 128 publications

Mitophagy: A Bridge Linking HMGB1 and Parkinson’s Disease Using Adult Zebrafish as a Model Organism

Mitophagy: A Bridge Linking HMGB1 and Parkinson’s Disease Using Adult Zebrafish as a Model Organism

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Treated Adult Zebrafish as a Model for Parkinson’s Disease

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

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