Neuroprotective effect of α-mangostin on mitochondrial dysfunction and α-synuclein aggregation in rotenone-induced model of Parkinson’s disease in differentiated SH-SY5Y cells

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

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The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress

Cells ◽

10.3390/cells10081874 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1874

Author(s):

Suwei Chen ◽

Sarah J. Annesley ◽

Rasha A. F. Jasim ◽

Paul R. Fisher

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Cysteine Residue ◽

Reduced Form ◽

Dependent Manner ◽

Loss Of Function ◽

Cellular Pathology

Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein’s ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity.

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Emerging neuroprotective effect of metformin in Parkinson’s disease: A molecular crosstalk

Pharmacological Research ◽

10.1016/j.phrs.2019.104593 ◽

2020 ◽

Vol 152 ◽

pp. 104593 ◽

Cited By ~ 9

Author(s):

Yam Nath Paudel ◽

Efthalia Angelopoulou ◽

Christina Piperi ◽

Mohd. Farooq Shaikh ◽

Iekhsan Othman

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroprotective Effect ◽

Molecular Crosstalk

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Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2529641 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Renrong Wei ◽

Cuiping Rong ◽

Qingfeng Xie ◽

Shouhai Wu ◽

Yuchao Feng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Calcium Binding ◽

Dopaminergic Neurons ◽

Neuroprotective Effect ◽

Interleukin 1 ◽

Mrna Levels ◽

Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

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