P4-164: Dimebon (Latrepirdine) protects from cell death-induced by mitochondrial stressors and alpha-synuclein over-expression, and decreases alpha-synuclein protein levels in a Parkinson's disease cell model.

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

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α-Synuclein Enhances Cadmium Uptake and Neurotoxicity via Oxidative Stress and Caspase Activated Cell Death Mechanisms in a Dopaminergic Cell Model of Parkinson’s Disease

Neurotoxicity Research ◽

10.1007/s12640-017-9725-x ◽

2017 ◽

Vol 32 (2) ◽

pp. 231-246 ◽

Cited By ~ 2

Author(s):

Weelic Chong ◽

Jessica Jiménez ◽

Matthew McIIvin ◽

Mak A. Saito ◽

Gunnar F. Kwakye

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Cell Model ◽

Cadmium Uptake ◽

Dopaminergic Cell ◽

Cell Death Mechanisms

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The molecular mechanisms underlying alpha-synuclein-evoked cell death; possible implications for the pathogenesis of Parkinson’s disease

Pharmacological Reports ◽

10.1016/s1734-1140(11)70650-8 ◽

2011 ◽

Vol 63 (5) ◽

pp. 1269

Author(s):

Agata Adamczyk ◽

Anna Kaźmierczak ◽

Grzegorz A. Czapski ◽

Joanna B. Strosznajder

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Molecular Mechanisms ◽

Alpha Synuclein

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Regulation of Actg1 and Gsta2 is possible mechanism by which capsaicin alleviates apoptosis in cell model of 6-OHDA-induced Parkinson's disease

Bioscience Reports ◽

10.1042/bsr20191796 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

Author(s):

Jiahui Liu ◽

Hong Liu ◽

Zhenxiang Zhao ◽

Jianfeng Wang ◽

Dandan Guo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Model ◽

Cell Damage ◽

Glutathione S Transferase ◽

Expression Arrays ◽

Transcriptional Changes ◽

Molecular Mechanism Of Action ◽

Disease Cell

Abstract The present study aimed to identify the gene expression changes conferred by capsaicin in the cell model of 6-OHDA-induced Parkinson's disease, to disclose the molecular mechanism of action of capsaicin. We used capsaicin-treated and paraffin-embedded wax blocks containing substantia nigra tissue from 6-OHDA-induced Parkinson's disease rats to analyze transcriptional changes using Affymetrix GeneChip Whole Transcript Expression Arrays. A total of 108 genes were differentially expressed in response to capsaicin treatment, and seven of these genes were selected for further analysis: Olr724, COX1, Gsta2, Rab5a, Potef, Actg1, and Acadsb, of which Actg1 (actin gamma 1) was down-regulated and Gsta2 (Glutathione S-transferase alpha 2) was up-regulated. We successfully overexpressed Actg1 and Gsta2 in vitro. CCK-8 detection and flow cytometry demonstrated that overexpression of Actg1 and Gsta2 increased apoptosis in the 6-OHDA-induced Parkinson's disease cell model. The imbalance between Actg1 and Gsta2 may be one of the mechanisms of cell damage in Parkinson's disease (PD). Capsaicin can protect the cells and reduce the apoptosis rate by regulating Actg1 and Gsta2.

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Ginsenoside Rg5 Alleviates 1-Methyl-4-Phenylpyridinium Ion Induced Parkinson's Disease Cell Model Damage by Regulating MicroRNA-874-3p/Thioredoxin Interacting Proteins Molecular Axis

10.36468/pharmaceutical-sciences.885 ◽

2021 ◽

Vol 83 (6) ◽

Author(s):

J. Zhang ◽

Zhao Rong ◽

Juan Hu ◽

X. Sun

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Model ◽

Molecular Axis ◽

Interacting Proteins ◽

Ginsenoside Rg5 ◽

Disease Cell

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Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.591475 ◽

2021 ◽

Vol 13 ◽

Author(s):

Anna Wilkaniec ◽

Anna M. Lenkiewicz ◽

Lidia Babiec ◽

Emilia Murawska ◽

Henryk M. Jęśko ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Fission ◽

Alpha Synuclein ◽

Post Translational Modifications ◽

Protein Levels ◽

Mitochondrial Homeostasis ◽

Mitochondrial Superoxide ◽

Mitochondrial Biosynthesis

Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson’s disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).

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