Parkinson's disease genetic mutations increase cell susceptibility to stress: Mutant α-synuclein enhances H2O2- and Sin-1-induced cell death

Cytokinins are adenine-based phytohormones that regulate key processes in plants, such as cell division and differentiation, root and shoot growth, apical dominance, branching, and seed germination. In preliminary studies, they have also shown protective activities against human neurodegenerative diseases. To extend knowledge of the protection (protective activity) they offer, we investigated activities of natural cytokinins against salsolinol (SAL)-induced toxicity (a Parkinson’s disease model) and glutamate (Glu)-induced death of neuron-like dopaminergic SH-SY5Y cells. We found that kinetin-3-glucoside, cis-zeatin riboside, and N6-isopentenyladenosine were active in the SAL-induced PD model. In addition, trans-, cis-zeatin, and kinetin along with the iron chelator deferoxamine (DFO) and the necroptosis inhibitor necrostatin 1 (NEC-1) significantly reduced cell death rates in the Glu-induced model. Lactate dehydrogenase assays revealed that the cytokinins provided lower neuroprotective activity than DFO and NEC-1. Moreover, they reduced apoptotic caspase-3/7 activities less strongly than DFO. However, the cytokinins had very similar effects to DFO and NEC-1 on superoxide radical production. Overall, they showed protective activity in the SAL-induced model of parkinsonian neuronal cell death and Glu-induced model of oxidative damage mainly by reduction of oxidative stress.

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Oxidative stress and regulated cell death in Parkinson’s disease

Ageing Research Reviews ◽

10.1016/j.arr.2021.101263 ◽

2021 ◽

Vol 67 ◽

pp. 101263

Author(s):

P.A. Dionísio ◽

J.D. Amaral ◽

C.M.P. Rodrigues

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Regulated Cell Death

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Plasma-borne indicators of inflammasome activity in Parkinson’s disease patients

npj Parkinson s Disease ◽

10.1038/s41531-020-00147-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Faith L. Anderson ◽

Katharine M. von Herrmann ◽

Angeline S. Andrew ◽

Yuliya I. Kuras ◽

Alison L. Young ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Nlrp3 Inflammasome ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Inflammasome Activation ◽

Membrane Pore ◽

Related Proteins ◽

Inflammasome Activity

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2018.00398 ◽

2018 ◽

Vol 12 ◽

Cited By ~ 18

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

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Cell Death in Parkinson’s Disease

Parkinson's Disease ◽

10.1201/9780203508596.ch42 ◽

2004 ◽

Author(s):

Richard Smeyne ◽

Ciaran Faherty

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death

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

International Journal of Molecular Sciences ◽

10.3390/ijms221810161 ◽

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.

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Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

10.1101/500629 ◽

2018 ◽

Author(s):

Michal Wegrzynowicz ◽

Dana Bar-On ◽

Laura Calo’ ◽

Oleg Anichtchik ◽

Mariangela Iovino ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Dopaminergic Neurons ◽

Dopamine Release ◽

Striatal Dopamine ◽

Substantia Nigra Pars Compacta ◽

Motor Deficit ◽

Promising Therapeutic Approach ◽

Striatal Dopamine Release

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761773 ◽

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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