Programmed cell death: Does it play a role in parkinson's disease?

1998 ◽  
Vol 44 (S1) ◽  
pp. S126-S133 ◽  
Author(s):  
Robert E. Burke ◽  
Nikolai G. Kholodilov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Programmed Cell Death

scholarly journals Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

2021 ◽  
Vol 22 (18) ◽  
pp. 10161
Author(s):  
Tapan Behl ◽  
Piyush Madaan ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Neelam Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Neurodegenerative Diseases ◽  
Hormone Receptors ◽  
Nerve Cells ◽  
Substantia Nigra Pars Compacta ◽  
Redox Equilibrium ◽  
Ppar Agonists

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.

scholarly journals Recapitulating Parkinson’s disease pathology in a three-dimensional neural cell culture model

2019 ◽  
Author(s):  
◽  
Teresa Rachel Taylor-Whiteley
Keyword(s):  
Parkinson’S Disease ◽  
Lipid Peroxidation ◽  
Cell Culture ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Culture Model ◽  
Cell Death Pathway ◽  
Culture Model ◽  
The Impact

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease (AD), occurring at a rate of 0.1%-0.2% of the population. The incidence of PD increases with advancing age, affecting 1% of the population over the age of 65. Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein (α-syn) into ubiquitin-positive Lewy bodies (LBs) represents a major neuropathological hallmark of PD. The impact of LB pathology on the disease pathogenesis is still largely unknown, with evidence suggesting small soluble oligomeric assemblies that precede LB development are the causative agent in PD. At present, the generation of large nuclear-associated LBs from endogenous wildtype α-syn, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming protocols. The primary objective of this thesis was to develop a more physiologically relevant cell culture model of PD that recapitulates the development of LB inclusions. Using a cell culture model of fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensions (3D), cells were shown to develop LB-like pathology upon exposure to exogenous α-syn species. In contrast to most cell- and rodent based PD models, which exhibit multiple diffuse α-syn aggregates throughout the cytoplasm, a single large nuclear inclusion that is immunopositive for α-syn and ubiquitin is rapidly obtained in our model. However, phosphorylation of α-syn within these inclusions was not observed. This was achieved without the need for overexpression of α-syn or genetic modification of the cell line. To further explore the mechanism of LB formation the recently discovered programmed cell death pathway ferroptosis was investigated. Ferroptosis is an irondependent cell death pathway that shares similar pathogenic features with PD including elevated iron concentration, GSH depletion, lipid peroxidation and increased ROS. However, there are currently no studies that have explored whether α-syn is involved in ferroptotic cell death. Viability assays within the 3D cell culture model following treatment with ferroptosis and apoptosis inducers and qPCR of ferroptotic targets demonstrated resistance to this mechanism of programmed cell death. Nevertheless, treatment with iron was associated with some features of ferroptosis including increased ROS, some lipid peroxidation and reduced levels of glutathione peroxidase 4 (GPX4). Phosphorylation of α-syn at serine 129 (S129) was increased upon iron treatment and reduced following treatment with a ferroptosis inhibitor, liproxstatin-1. These results demonstrate the potential implications of iron exposure, α-syn aggregation, and ferroptosis in the pathogenesis of PD. The system described in this thesis provides an ideal tool to screen compounds to intervene therapeutically in LB formation, and to investigate the mechanisms involved in disease progression in synucleinopathies.

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