The Role of NOX4 in Parkinson’s Disease with Dementia

The neuropathology of Parkinson’s disease with dementia (PDD) has been reported to involve heterogeneous and various disease mechanisms. Alpha-synuclein (α-syn) and amyloid beta (Aβ) pathology are associated with the cognitive status of PDD, and NADPH oxidase (NOX) is known to affect a variety of cognitive functions. We investigated the effects of NOX on cognitive impairment and on α-syn and Aβ expression and aggregation in PDD. In the 6-hydroxydopamine (6-OHDA)-injected mouse model, cognitive and motor function, and the levels of α-syn, Aβ, and oligomer A11 after inhibition of NOX4 expression in the hippocampal dentate gyrus (DG) were measured by the Morris water maze, novel object recognition, rotation, and rotarod tests, as well as immunoblotting and immunohistochemistry. After 6-OHDA administration, the death of nigrostriatal dopamine neurons and the expression of α-syn and NOX1 in the substantia nigra were increased, and phosphorylated α-syn, Aβ, oligomer A11, and NOX4 were upregulated in the hippocampus. 6-OHDA dose-dependent cognitive impairment was observed, and the increased cognitive impairment, Aβ expression, and oligomer A11 production in 6-OHDA-treated mice were suppressed by NOX4 knockdown in the hippocampal DG. Our results suggest that increased expression of NOX4 in the hippocampal DG in the 6-OHDA-treated mouse induces Aβ expression and oligomer A11 production, thereby reducing cognitive function.

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Modeling of Parkinson's disease on D. melanogaster: oxidative stress and the role of isogenization of transgenic lines

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v22.922 ◽

2018 ◽

Vol 22 ◽

pp. 46-50

Author(s):

Kh. A. Dronska ◽

Kh. M. Yavdyk ◽

O. H. Stasyk ◽

N. P. Matiytsiv

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Dopamine Neurons ◽

Significant Difference ◽

Before And After ◽

Transgenic Lines ◽

Stress Susceptibility

Aim. Oxidative stress (OS) is considered one of the main factors that leads to the degeneration of dopamine neurons in Parkinson's disease (PD). The purpose of the work was to test sensitivity to the conditions of the OS of D. melanogaster individuals with expression of human alpha-synuclein in neurons UAS-SNCA/elavGal4; and establish the role of the isogenization of the lines derived from stock collections in the study of this phenotype. Methods. For the isogenyzation of the line, we conducted five generations of sequential crossings of individuals with insertion of human alpha synuclein gene into the w1118 line. A 4-day test using H2O2 as prooxidant was used to test the sensitivity to OS conditions. Results. Individuals with expression of alpha-synuclein gene in neurons were characterized by statistically significant sensitivity to OS conditions, compared with controls. Also, there was a significant difference in the degree of sensitivity to the OS in the second day of the experiment in individuals before and after the isogenization of the effector line. Conclusions. Hypersensitivity to the OS is detected as a specific phenotype under conditions of expression of human alpha-synuclein in Drosophila neurons. The importance of the isogenization of transgenic lines for the characterization of the stress susceptibility phenotype is established.Keywords: Drosophila melanogaster, alpha-synuclein, oxidative stress, isogenization.

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Faculty Opinions recommendation of The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371031.14741147 ◽

2011 ◽

Author(s):

Keith Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Drosophila Model

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The Protective Role of Brain CYP2J in Parkinson’s Disease Models

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2917981 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Yueran Li ◽

Jinhua Wu ◽

Xuming Yu ◽

Shufang Na ◽

Ke Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Brain Regions ◽

Protective Role ◽

Neural Cells ◽

Endogenous Substrates ◽

6 Hydroxydopamine ◽

Myd88 Signaling ◽

Lps Treatment

CYP2J proteins are present in the neural cells of human and rodent brain regions. The aim of this study was to investigate the role of brain CYP2J in Parkinson’s disease. Rats received right unilateral injection with lipopolysaccharide (LPS) or 6-hydroxydopamine (6-OHDA) in the substantia nigra following transfection with or without the CYP2J3 expression vector. Compared with LPS-treated rats, CYP2J3 transfection significantly decreased apomorphine-induced rotation by 57.3% at day 12 and 47.0% at day 21 after LPS treatment; moreover, CYP2J3 transfection attenuated the accumulation of α-synuclein. Compared with the 6-OHDA group, the number of rotations by rats transfected with CYP2J3 decreased by 59.6% at day 12 and 43.5% at day 21 after 6-OHDA treatment. The loss of dopaminergic neurons and the inhibition of the antioxidative system induced by LPS or 6-OHDA were attenuated following CYP2J3 transfection. The TLR4-MyD88 signaling pathway was involved in the downregulation of brain CYP2J induced by LPS, and CYP2J transfection upregulated the expression of Nrf2 via the inhibition of miR-340 in U251 cells. The data suggest that increased levels of CYP2J in the brain can delay the pathological progression of PD initiated by inflammation or neurotoxins. The alteration of the metabolism of the endogenous substrates (e.g., AA) could affect the risk of neurodegenerative disease.

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Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽

10.1039/c5ra13546j ◽

2015 ◽

Vol 5 (95) ◽

pp. 77706-77715 ◽

Cited By ~ 4

Author(s):

Supinder Kaur ◽

Aamir Nazir

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Potential Role ◽

Alpha Synuclein ◽

C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

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Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

10.1101/470476 ◽

2018 ◽

Cited By ~ 7

Author(s):

Tim E. Moors ◽

Christina A. Maat ◽

Daniel Niedieker ◽

Daniel Mona ◽

Dennis Petersen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Distribution Patterns ◽

Alpha Synuclein ◽

Label Free ◽

Post Translational Modifications ◽

Sted Microscopy ◽

C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

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Difference of the role of high cortisol levels in the cognitive impairment Parkinson’s Disease and vascular Parkinsonism

Journal of the Neurological Sciences ◽

10.1016/j.jns.2019.10.1358 ◽

2019 ◽

Vol 405 ◽

pp. 285

Author(s):

D. Akramova ◽

G. Rakhimbaeva

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Vascular Parkinsonism ◽

Cortisol Levels

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Role of increased levels of endothelial factors in cognitive impairment in the Parkinson’s disease and vascular parkinsonism

Journal of the Neurological Sciences ◽

10.1016/j.jns.2019.10.1366 ◽

2019 ◽

Vol 405 ◽

pp. 288-289

Author(s):

D. Akramova ◽

G. Rakhimbaeva

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Vascular Parkinsonism ◽

Endothelial Factors

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Functional Crosstalk between CB and TRPV1 Receptors Protects Nigrostriatal Dopaminergic Neurons in the MPTP Model of Parkinson’s Disease

Journal of Immunology Research ◽

10.1155/2020/5093493 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Rayul Wi ◽

Young Cheul Chung ◽

Byung Kwan Jin ◽

Lihua Duan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Significant Loss ◽

Glial Activation ◽

Dopamine Neurons ◽

Pcr Analysis ◽

Beneficial Effects ◽

Nigrostriatal Dopamine ◽

Nigrostriatal Dopamine Neurons

The present study examined whether crosstalk between cannabinoid (CB) and transient potential receptor vanilloid type 1 (TRPV1) could contribute to the survival of nigrostriatal dopamine neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD). MPTP induced a significant loss of nigrostriatal dopamine neurons and glial activation in the substantia nigra (SN) and striatum (STR) as visualized by tyrosine hydroxylase (TH) or macrophage antigen complex-1 (MAC-1) or glial fibrillary acidic protein (GFAP) immunocytochemistry, respectively. RT-PCR analysis shows the upregulation of inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α in microglia in the SN in vivo, indicating the activation of the inflammatory system. By contrast, treatment with capsaicin (a specific TRPV1 agonist) increased the survival of dopamine neurons in the SN and their fibers and dopamine levels in the STR in MPTP mice. Capsaicin neuroprotection is accompanied by inhibiting MPTP-induced glial activation and production of inflammatory cytokines. Treatment with AM251 and AM630 (CB1/2 antagonists) abolished capsaicin-induced beneficial effects, indicating the existence of a functional crosstalk between CB and TRPV1. Moreover, treatment with anandamide (an endogenous agonist for both CB and TRVP1) rescued nigrostriatal dopamine neurons and reduced gliosis-derived neuroinflammatory responses in MPTP mice. These results suggest that the cannabinoid and vanilloid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with neuroinflammation.

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Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease

Brain Sciences ◽

10.3390/brainsci9040073 ◽

2019 ◽

Vol 9 (4) ◽

pp. 73 ◽

Cited By ~ 7

Author(s):

Anthony Gaeta ◽

Kim Caldwell ◽

Guy Caldwell

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Dopamine Neurons ◽

Genetic Modifiers ◽

Transgenic Expression ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Cellular Phenotypes ◽

Functional Mechanisms

Parkinson’s Disease (PD) is the second-most common neurodegenerative disease in the world, yet the fundamental and underlying causes of the disease are largely unknown, and treatments remain sparse and impotent. Several biological systems have been employed to model the disease but the nematode roundworm Caenorhabditis elegans (C. elegans) shows unique promise among these to disinter the elusive factors that may prevent, halt, and/or reverse PD phenotypes. Some of the most salient of these C. elegans models of PD are those that position the misfolding-prone protein alpha-synuclein (α-syn), a hallmark pathological component of PD, as the primary target for scientific interrogation. By transgenic expression of human α-syn in different tissues, including dopamine neurons and muscle cells, the primary cellular phenotypes of PD in humans have been recapitulated in these C. elegans models and have already uncovered multifarious genetic factors and chemical compounds that attenuate dopaminergic neurodegeneration. This review describes the paramount discoveries obtained through the application of different α-syn models of PD in C. elegans and highlights their established utility and respective promise to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets and molecular leads for PD with the potential to translate to humans.

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