Targeting Alpha-Synuclein as a Therapy for Parkinson’s Disease

Frontiers in Molecular Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: Dec. 5, 2019

Parkinson's disease is one of the most common neurodegenerative disorders with a global burden approximately 6.1 million patients. Alpha-synuclein has been linked to both sporadic and familial forms disease. Moreover, alpha-synuclein present in Lewy-bodies, neuropathological hallmark disease, theis protein its aggregation have widely neurotoxic pathways that ultimately lead neurodegeneration. Such include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, endoplasmic reticulum oxidative stress. not only shown alter cellular pathways, but also spread between cells, causing host cells. Therapeutic approaches will need address several, if all, these angles toxicity. Here we review current advances therapeutic efforts for aim produce modifying therapy by targeting spread, production, aggregation, degradation alpha-synuclein. These include: receptor blocking strategies whereby putative receptors could be blocked inhibiting reduction which decrease amount available pathway use small molecules order target immunotherapy increase increasing flux. The research discussed here may tackles onset progression future.

Language: Английский

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Therapeutic approaches to target alpha-synuclein pathology

Experimental Neurology, Journal Year: 2017, Volume and Issue: 298, P. 225 - 235

Published: Oct. 10, 2017

Language: Английский

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Targeting Microglia for Therapy of Parkinson’s Disease by Using Biomimetic Ultrasmall Nanoparticles

Journal of the American Chemical Society, Journal Year: 2020, Volume and Issue: 142(52), P. 21730 - 21742

Published: Dec. 14, 2020

Microglia as an important type of innate immune cell in the brain have been considered effective therapeutic target for treatment central nervous degenerative diseases. Herein, we report membrane coated novel biomimetic Cu2–xSe-PVP-Qe nanoparticles (denoted CSPQ@CM nanoparticles, where PVP is poly(vinylpyrrolidone), Qe quercetin, and CM neuron cells) effectively targeting modulating microglia to treat Parkinson's disease (PD). The CSPQ exhibit multienzyme activities could scavenge reactive oxygen species promote polarization into anti-inflammatory M2-like phenotype relieve neuroinflammation. We reveal that targeted through specific interactions between surface vascular cells adhering molecule-1 α4β1 integrin expressed by microglia. They significantly improve symptoms PD mice result excellent efficacy, evidenced recovery their dopamine level cerebrospinal fluid, tyrosine hydroxylase, ionized calcium binding adapter protein 1 normal levels. Our work demonstrates great potential these robust other

Language: Английский

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Therapeutics in the Pipeline Targetingα-Synuclein for Parkinson's Disease

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(1), P. 207 - 237

Published: Jan. 1, 2022

Parkinson9s disease (PD) is the second most common neurodegenerative disorder and fastest growing neurologic in world, yet no disease-modifying therapy available for this disabling condition. Multiple lines of evidence implicate protein α-synuclein (α-Syn) pathogenesis PD, as such, there intense interest targeting α-Syn potential modification. also a key pathogenic other synucleionpathies, commonly dementia with Lewy bodies. Thus, therapeutics will have utility these disorders well. Here we discuss various approaches that are being investigated to prevent mitigate toxicity including clearing its pathologic aggregates from brain using immunization strategies, inhibiting misfolding aggregation, reducing expression level, enhancing cellular clearance mechanisms, preventing cell-to-cell transmission within perhaps periphery, proteins associated or implicated PD contribute toxicity. We pipeline harness strategies. Finally, challenges opportunities field discovery development modification PD.

Significance Statement

disorder, which therapies remain major unmet need. A large body points well bodies, making it leading therapeutic interest. This review discusses progress made date toward discovering developing would slow stop progression diseases.

Language: Английский

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Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Science Advances, Journal Year: 2023, Volume and Issue: 9(9)

Published: March 1, 2023

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation not fully understood. We here show that mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part this process. MPC transports into mitochondria, linking cytosolic glycolysis tricarboxylic acid cycle oxidative phosphorylation. Despite metabolic key function, of NSPCs has been addressed. quiescent have an active express high levels MPC. Pharmacological inhibition increases aspartate triggers NSPC activation. Furthermore, genetic Mpc1 ablation vitro vivo also activates NSPCs, which differentiate mature neurons, leading overall increased hippocampal neurogenesis aged mice. These findings highlight importance regulation identify pathway through import controls

Language: Английский

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Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Movement Disorders, Journal Year: 2018, Volume and Issue: 33(5), P. 684 - 696

Published: April 27, 2018

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. discovery genetic variants causing and/or increasing risk for PD has provided field with a new arsenal potential therapies ready to be tested clinical trials. We highlight 3 discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) have prompted therapeutic approaches now entering stages. are at an exciting juncture journey developing disease-modifying based on knowledge genetics pathology. This review focuses paradigms under development highlights wide range key outstanding questions PD. © 2018 Authors. Movement Disorders published by Wiley Periodicals, Inc. behalf International Parkinson Disorder Society.

Language: Английский

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Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death

The Journal of Cell Biology, Journal Year: 2017, Volume and Issue: 216(4), P. 1091 - 1105

Published: March 2, 2017

Glutamate is the dominant excitatory neurotransmitter in brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation amino acid receptors well studied, minimal consideration has been given targeting mitochondrial glutamate metabolism control Here we demonstrate that chemical inhibition pyruvate carrier (MPC) protects primary cortical neurons from death. Reductions uptake do not compromise cellular energy metabolism, suggesting neuronal flexibility. Rather, MPC rewires substrate preferentially increase reliance on fuel energetics and anaplerosis. Mobilizing pool for oxidation decreases quantity released upon depolarization and, turn, limits positive-feedback cascade injury. The finding links glutamatergic neurotransmission establishes as a therapeutic target treat neurodegenerative diseases characterized by excitotoxicity.

Language: Английский

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Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer

Nature Metabolism, Journal Year: 2018, Volume and Issue: 1(1), P. 70 - 85

Published: Nov. 14, 2018

Language: Английский

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Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells

Science Signaling, Journal Year: 2019, Volume and Issue: 12(563)

Published: Jan. 8, 2019

Exosomes containing the adaptor ASC spread NLRP3 inflammasome activation between cells after manganese exposure.

Language: Английский

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Attenuation of TNF-α-Induced Inflammatory Injury in Endothelial Cells by Ginsenoside Rb1 via Inhibiting NF-κB, JNK and p38 Signaling Pathways

Frontiers in Pharmacology, Journal Year: 2017, Volume and Issue: 8

Published: Aug. 2, 2017

It is currently believed that inflammation plays a central role in the pathophysiology of atherosclerosis (AS). Oxidative stress and redox-sensitive transcription factors are implicated process. Ginsenoside Rb1, major active ingredient processed Radix notoginseng, has attracted widespread attention because its potential to improve cardiovascular function. However, effects ginsenoside Rb1 on tumor necrosis factor α (TNF-α)-induced vascular endothelial cell injury underlying molecular mechanisms have never been studied. This study showed TNF-α-induced oxidative stress, apoptosis human umbilical vein cells (HUVECs) could be attenuated by pretreatment. Using JC-1, Annexin V/PI TUNEL staining, caspase-3 activity assay, we found provided significant protection against death. Furthermore, pretreatment inhibit ROS MDA production; increase activities SOD, CAT GSH-Px; decrease levels IL-1β, IL-6, VCAM-1, ICAM-1, VEGF, MMP-2 MMP-9. Importantly, cytoprotective were correlated with NF-κB signaling pathway inhibition. Additionally, may suppress through p-38 JNK activation, findings supported results our experiments involving anisomycin (AM), p38 activator. In conclusion, this protects HUVECs from inhibiting p38. inhibition suppressed down-regulated expression inflammatory apoptosis-related proteins.

Language: Английский

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