scholarly journals Metabolic demand regulates selective cell death in Parkinson′s Disease

2021 ◽  
Author(s):  
Ishaan S Nanal ◽  
Linxi Wang ◽  
Luke Y Zhao ◽  
Andrew Looka ◽  
Marianne Bezaire
Keyword(s):  
Cell Death ◽  
Single Neuron ◽  
Therapeutic Strategy ◽  
Calcium Influx ◽  
Metabolic Stress ◽  
Selective Vulnerability ◽  
Substantia Nigra Pars Compacta ◽  
Metabolic Demand ◽  
Channel Inhibition ◽  
The World

Parkinson′s Disease (PD) is a debilitating neurodegenerative condition that affects over 10 million people across the world, causing tremors and muscle weakness. Its mechanisms are unknown, but one key feature is selective cell death: neurons in the Substantia Nigra Pars Compacta (SNc) die, but their neighbors, the cells in the Ventral Tegmental Area (VTA), remain healthy. To study this phenomenon, we used an established single neuron model of the SNc, adapting its biophysical and bioenergetic properties to match that of the VTA. We discovered that reducing calcium influx correlates with higher ATP and lower ROS concentrations in the cell, suggesting in silico the importance of calcium influx in metabolic stress and selective vulnerability for Parkinson′s Disease. Future efforts may target calcium channel inhibition as a therapeutic strategy, although caution is needed with potential metabolic side effects.

CSIG-23. ELONGATION CONTROL OF mRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi38-vi38
Author(s):  
Alberto Delaidelli ◽  
Gian Luca Negri ◽  
Betty Yao ◽  
Que Xi Wang ◽  
Yue Zhou Huang ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Large Scale ◽  
Metabolic Stress ◽  
Mrna Translation ◽  
Nutrient Deprivation ◽  
Mrna Levels ◽  
Metabolic Demand ◽  
Translation Elongation ◽  
Group 3

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p< 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.

scholarly journals Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1490
Author(s):  
Osama M. Elzamzamy ◽  
Brandon E. Johnson ◽  
Wei-Chih Chen ◽  
Gangqing Hu ◽  
Reinhold Penner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Transient Receptor Potential ◽  
Cyclic Peptide ◽  
Calcium Influx ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Prognostic Indicators ◽  
Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

scholarly journals Attenuation of inhibitory PAS domain protein-induced cell death by synthetic peptides derived from Mcl-1 transmenbrane domain

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuya Kasai ◽  
Ken-ichi Yasumoto ◽  
Kazuhiro Sogawa
Keyword(s):  
Cell Death ◽  
Synthetic Peptides ◽  
Specific Binding ◽  
Neuronal Cell ◽  
Chimeric Protein ◽  
Substantia Nigra Pars Compacta ◽  
Pas Domain ◽  
Domain Protein ◽  
Tm Domain ◽  
Apoptotic Activity

AbstractExpression of Inhibitory PAS domain protein (IPAS) induces apoptosis by inhibiting the anti-apoptotic activity of mitochondrial pro-survival proteins including Bcl-xL and Mcl-1 through direct binding. Analysis to examine the IPAS-binding region in Bcl-xL demonstrated that the C-terminal transmembrane (TM) domain is indispensable for the specific binding. A chimeric protein composed of the TM domain of Mcl-1 fused to the C-terminus of Citrine also exhibited a binding affinity to IPAS, and markedly attenuated apoptosis caused by the overexpression of Cerulean-IPAS in SH-SY5Y cells. HIV-1 TAT cell-penetrating peptide-conjugated synthetic peptides that cover whole or parts of the Mcl-1 TM domain showed anti-apoptotic activity in the CoCl2-induced cell death in PC12 cells. Administration of these highly effective anti-apoptotic peptides to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that produces a reliable mouse model of Parkinson’s disease (PD) decreased neuronal cell loss in the substantia nigra pars compacta. Therefore, the peptides may be considered promising therapeutic agents for neurodegenerative disorders such as PD and stroke.

scholarly journals microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

2018 ◽  
Vol 115 (46) ◽  
pp. E10849-E10858 ◽  
Author(s):  
Yan Li ◽  
Jingjing Jiang ◽  
Wei Liu ◽  
Hui Wang ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Death ◽  
Cell Fate ◽  
Metabolic Regulation ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Stress ◽  
Muscle Weight ◽  
Dependent Protein ◽  
Metabolic Checkpoints

The metabolic regulation of cell death is sophisticated. A growing body of evidence suggests the existence of multiple metabolic checkpoints that dictate cell fate in response to metabolic fluctuations. However, whether microRNAs (miRNAs) are able to respond to metabolic stress, reset the threshold of cell death, and attempt to reestablish homeostasis is largely unknown. Here, we show that miR-378/378* KO mice cannot maintain normal muscle weight and have poor running performance, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis in skeletal muscle, whereas miR-378 overexpression is able to enhance autophagy and repress apoptosis in skeletal muscle of mice. Our in vitro data show that metabolic stress-responsive miR-378 promotes autophagy and inhibits apoptosis in a cell-autonomous manner. Mechanistically, miR-378 promotes autophagy initiation through the mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase 1 (ULK1) pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1). Meanwhile, miR-378 suppresses intrinsic apoptosis initiation directly through targeting an initiator caspase—Caspase 9. Thus, we propose that miR-378 is a critical component of metabolic checkpoints, which integrates metabolic information into an adaptive response to reduce the propensity of myocytes to undergo apoptosis by enhancing the autophagic process and blocking apoptotic initiation. Lastly, our data suggest that inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy.

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 Skin and Gut Microbiome in Psoriasis: Gaining Insight Into the Pathophysiology of It and Finding Novel Therapeutic Strategies

2020 ◽  
Vol 11 ◽  
Author(s):  
Lihui Chen ◽  
Jie Li ◽  
Wu Zhu ◽  
Yehong Kuang ◽  
Tao Liu ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Therapeutic Strategies ◽  
Intestinal Microbiome ◽  
Core Microbiome ◽  
The Core ◽  
The World ◽  
Novel Therapeutic Strategies ◽  
Insight Into ◽  
Gaining Insight

Psoriasis affects the health of myriad populations around the world. The pathogenesis is multifactorial, and the exact driving factor remains unclear. This condition arises from the interaction between hyperproliferative keratinocytes and infiltrating immune cells, with poor prognosis and high recurrence. Better clinical treatments remain to be explored. There is much evidence that alterations in the skin and intestinal microbiome play an important role in the pathogenesis of psoriasis, and restoration of the microbiome is a promising preventive and therapeutic strategy for psoriasis. Herein, we have reviewed recent studies on the psoriasis-related microbiome in an attempt to confidently identify the “core” microbiome of psoriasis patients, understand the role of microbiome in the pathogenesis of psoriasis, and explore new therapeutic strategies for psoriasis through microbial intervention.

scholarly journals Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

2020 ◽  
Author(s):  
Bo Li ◽  
Ting Zhang ◽  
Wei Liu ◽  
Yekai Wang ◽  
Rong Xu ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Lipid Synthesis ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
High Energy ◽  
Metabolic Dysfunction ◽  
Metabolic Demand ◽  
Energy Demands

AbstractPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

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

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.

scholarly journals KDM6A mediated expression of the long noncoding RNA DINO causes TP53 tumor suppressor stabilization in Human Papillomavirus type 16 E7 expressing cells

2020 ◽  
Author(s):  
Surendra Sharma ◽  
Karl Munger
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Critical Role ◽  
Metabolic Stress ◽  
Dominant Negative ◽  
Missing Link ◽  
Hpv16 E6 ◽  
E6 And E7

ABSTRACTHPV16 E7 has long been noted to stabilize the TP53 tumor suppressor. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure and can occur independent of E2F regulated MDM2 inhibitor, p14ARF. Here, we report that the Damage Induced Noncoding (DINO) lncRNA (DINOL) is the missing link between HPV16 E7 and increased TP53 levels. DINO levels are decreased in cells where TP53 is inactivated, either by HPV16 E6, expression of a dominant negative TP53 minigene or by TP53 depletion. DINO levels are increased in HPV16 E7 expressing cells. HPV16 E7 causes increased DINO expression independent of RB1 degradation and E2F1 activation. Similar to the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase, KDM6A. DINO stabilizes TP53 in HPV16 E7 expressing cells and as a TP53 transcriptional target, DINO levels further increase. Similar to other oncogenes such as adenovirus E1A or MYC, HPV16 E7 expressing cells are sensitized to cell death under conditions of metabolic stress and in the case of E7, this has been linked to TP53 activation. Consistent with earlier studies, we show that HPV16 E7 expressing keratinocytes are highly sensitive to metabolic stress induced by the antidiabetic drug, metformin. Metformin sensitivity of HPV16 E7 expressing cells is rescued by DINO depletion. This work identifies DINO as a critical mediator TP53 stabilization and activation in HPV16 E7 expressing cells.IMPORTANCEViral oncoproteins, including HPV16 E6 and E7 have been instrumental in elucidating the activities of cellular signaling networks including those governed by the TP53 tumor suppressor. Our study demonstrates that the long noncoding RNA DINO is the long sought missing link between HPV16 E7 and elevated TP53 levels. Importantly, the TP53 stabilizing DINO plays a critical role in the predisposition of HPV16 E7 expressing cells to cell death under metabolic stress conditions from metformin treatment.

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