scholarly journals Herbal medicine (Hepad) prevents dopaminergic neuronal death in the rat MPTP model of Parkinson’s disease

2019 ◽  
Vol 8 (3) ◽  
pp. 202-208
Author(s):  
Dong Hee Kim ◽  
Jeong June Choi ◽  
Byung-Jun Park
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Herbal Medicine ◽  
Neuronal Death ◽  
Mptp Model

scholarly journals Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benedict Tanudjojo ◽  
Samiha S. Shaikh ◽  
Alexis Fenyi ◽  
Luc Bousset ◽  
Devika Agarwal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Neuronal Death ◽  
Dopaminergic Neurons ◽  
De Novo ◽  
Dependent Manner ◽  
Human Neurons ◽  
Phenotypic Manifestation ◽  
Induced Aggregation

Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.

scholarly journals Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

2021 ◽  
Vol 22 (12) ◽  
pp. 6277
Author(s):  
Joanna A. Motyl ◽  
Joanna B. Strosznajder ◽  
Agnieszka Wencel ◽  
Robert P. Strosznajder
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Fate ◽  
Neuronal Death ◽  
Neurological Diseases ◽  
Alpha Synuclein ◽  
Lipid Mediator ◽  
Cell Defense ◽  
Promising Therapeutic Approach ◽  
S1p Receptor

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

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.

Strain-dependent recovery of open-field behavior and striatal dopamine deficiency in the mouse MPTP model of Parkinson’s disease

1999 ◽  
Vol 1 (1) ◽  
pp. 41-56 ◽  
Author(s):  
Rainer K. W. Schwarting ◽  
Marco Sedelis ◽  
Katja Hofele ◽  
Georg W. Auburger ◽  
Joseph P. Huston
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Open Field ◽  
Striatal Dopamine ◽  
Open Field Behavior ◽  
Field Behavior ◽  
Mptp Model ◽  
Strain Dependent

scholarly journals Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease

2018 ◽  
Vol 12 ◽  
Author(s):  
Irene García-Domínguez ◽  
Karolina Veselá ◽  
Juan García-Revilla ◽  
Alejandro Carrillo-Jiménez ◽  
María Angustias Roca-Ceballos ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Peripheral Inflammation ◽  
Dopaminergic Cell ◽  
Mptp Model

scholarly journals Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

2016 ◽  
Vol 24 (7) ◽  
pp. 376-391 ◽  
Author(s):  
Emma Deas ◽  
Nunilo Cremades ◽  
Plamena R. Angelova ◽  
Marthe H.R. Ludtmann ◽  
Zhi Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ions ◽  
Neuronal Death ◽  
Alpha Synuclein

scholarly journals TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin He ◽  
Yue Xie ◽  
Qiongping Zheng ◽  
Zeyu Zhang ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Essential Role ◽  
Dopaminergic Neurodegeneration ◽  
Promising Strategy ◽  
Progressive Loss ◽  
Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

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