Protein Misfolding, Mitochondrial Disturbances, And Kynurenines In The Pathogenesis Of Neurodegenerative Disorders

2009 ◽  
pp. 452-472
Author(s):  
Gabriella Gárdián ◽  
Katalin Sas ◽  
József Toldi ◽  
László Vécsei
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding

Purines and Pyrimidines: Metabolism, Function and Potential as therapeutic options in neurodegenerative diseases

2020 ◽  
Vol 21 ◽  
Author(s):  
Debanjan Kundu ◽  
Vikash Kumar Dubey
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Treatment Regimens ◽  
Loss Of Balance ◽  
Current Scenario ◽  
Unexplored Area ◽  
Molecular Origin ◽  
Purines And Pyrimidines

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

scholarly journals Inactivation of Prions by Low-Temperature Sterilization Technology Using Vaporized Gas Derived from a Hydrogen Peroxide–Peracetic Acid Mixture

Pathogens ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 24
Author(s):  
Akikazu Sakudo ◽  
Daiki Anraku ◽  
Tomomasa Itarashiki
Keyword(s):  
Hydrogen Peroxide ◽  
Medical Devices ◽  
Neurodegenerative Disorders ◽  
Peracetic Acid ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Proteinase K ◽  
Acid Mixture ◽  
Cover Glass ◽  
Standard Mode

Prion diseases are proteopathies that cause neurodegenerative disorders in humans and animals. Prion is highly resistant to both chemical and physical inactivation. Here, vaporized gas derived from a hydrogen peroxide–peracetic acid mixture (VHPPA) was evaluated for its ability to inactivate prion using a STERIACE 100 instrument (Saraya Co., Ltd.). Brain homogenates of scrapie (Chandler strain) prion-infected mice were placed on a cover glass, air-dried, sealed in a Tyvek package, and subjected to VHPPA treatment at 50–55 °C using 8% hydrogen peroxide and <10% peracetic acid for 47 min (standard mode, SD) or 30 min (quick mode, QC). Untreated control samples were prepared in the same way but without VHPPA. The resulting samples were treated with proteinase K (PK) to separate PK-resistant prion protein (PrPres), as a marker of the abnormal isoform (PrPSc). Immunoblotting showed that PrPres was reduced by both SD and QC VHPPA treatments. PrPres bands were detected after protein misfolding cyclic amplification of control but not VHPPA-treated samples. In mice injected with prion samples, VHPPA treatment of prion significantly prolonged survival relative to untreated samples, suggesting that it decreases prion infectivity. Taken together, the results show that VHPPA inactivates prions and might be applied to the sterilization of contaminated heat-sensitive medical devices.

scholarly journals Catechins as Tools to Understand the Molecular Basis of Neurodegeneration

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3571
Author(s):  
Karla Martinez Pomier ◽  
Rashik Ahmed ◽  
Giuseppe Melacini
Keyword(s):  
Phenolic Compounds ◽  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Parkinson’S Diseases ◽  
Pharmacokinetic Properties ◽  
Self Association

Protein misfolding as well as the subsequent self-association and deposition of amyloid aggregates is implicated in the progression of several neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Modulators of amyloidogenic aggregation serve as essential tools to dissect the underlying molecular mechanisms and may offer insight on potential therapeutic solutions. These modulators include green tea catechins, which are potent inhibitors of amyloid aggregation. Although catechins often exhibit poor pharmacokinetic properties and bioavailability, they are still essential tools for identifying the drivers of amyloid aggregation and for developing other aggregation modulators through structural mimicry. As an illustration of such strategies, here we review how catechins have been used to map the toxic surfaces of oligomeric amyloid-like species and develop catechin-based phenolic compounds with enhanced anti-amyloid activity.

scholarly journals Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

2019 ◽  
Vol 20 (4) ◽  
pp. 901 ◽  
Author(s):  
Stefano Thellung ◽  
Alessandro Corsaro ◽  
Mario Nizzari ◽  
Federica Barbieri ◽  
Tullio Florio
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Mammalian Target Of Rapamycin ◽  
Misfolded Proteins ◽  
Autophagic Flux ◽  
Suppressor Activity ◽  
Self Defense ◽  
Intracellular Content ◽  
Trophic Factor Deprivation ◽  
Degraded Material

The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers’ clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential.

scholarly journals Disulfide Bonding in Neurodegenerative Misfolding Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Francesca Mossuto
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Disulfide Bonds ◽  
Protein Misfolding ◽  
Bond Formation ◽  
Specific Protein ◽  
Disulfide Bonding ◽  
Misfolding Diseases ◽  
Protein Misfolding And Aggregation

In recent years an increasing number of neurodegenerative diseases has been linked to the misfolding of a specific protein and its subsequent accumulation into aggregated species, often toxic to the cell. Of all the factors that affect the behavior of these proteins, disulfide bonds are likely to be important, being very conserved in protein sequences and being the enzymes devoted to their formation among the most conserved machineries in mammals. Their crucial role in the folding and in the function of a big fraction of the human proteome is well established. The role of disulfide bonding in preventing and managing protein misfolding and aggregation is currently under investigation. New insights into their involvement in neurodegenerative diseases, their effect on the process of protein misfolding and aggregation, and into the role of the cellular machineries devoted to disulfide bond formation in neurodegenerative diseases are emerging. These studies mark a step forward in the comprehension of the biological base of neurodegenerative disorders and highlight the numerous questions that still remain open.

scholarly journals Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

2021 ◽  
Author(s):  
Priyanka Sengupta ◽  
Debashis Mukhopadhyay
Keyword(s):  
Oxidative Stress ◽  
Growth Hormone ◽  
Neurodegenerative Diseases ◽  
Insulin Receptor ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Combinatorial Therapy ◽  
Insulin Pathway ◽  
Insulin Dysregulation ◽  
Receptor Family

RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incretin based therapies that have gradually emerged as alternatives for insulin based therapy due to its inherent drawback of resistance has been briefly discussed.

scholarly journals Review on various factors responsible for neurodegenerative disorders

2021 ◽  
Vol 16 (1) ◽  
pp. 126-132
Author(s):  
Harshwardhan J Tembhurnikar ◽  
Neha D Thool ◽  
Rasika J Patil ◽  
Ranjita K Das
Keyword(s):  
Oxidative Stress ◽  
Nervous System ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Critical Role ◽  
Structure And Function ◽  
Neuronal Structure ◽  
Pathophysiological Mechanisms ◽  
Neurological Illnesses ◽  
And Function

Neurodegenerative disorders are nervous system disorders that result in the loss of neuronal structure and function. As shown in Alzheimer's and Parkinson's disease, these changes cause a loss of various capacities, including cognition and mobility. Several factors have been discovered to play a critical role in the etiology of common neurological illnesses, including oxidative stress and protein misfolding. It's still unclear if these factors cause or contribute to the progression of the illnesses. Despite efforts to understand the molecular and pathophysiological mechanisms behind these pathways, many aspects remain unknown. The goal of this review is to investigate the numerous factors linked to neurodegeneration.

scholarly journals Molecular mechanisms of proteinopathies across neurodegenerative disease: a review

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Alexander P. Marsh
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Current Data ◽  
Main Body ◽  
Molecular Events ◽  
Underlying Pathology

Abstract Background Although there is a range of different symptoms across neurodegenerative diseases, they have been noted to have common pathogenic features. An archetypal feature shared between these diseases is protein misfolding; however, the mechanism behind the proteins abnormalities is still under investigation. There is an emerging hypothesis in the literature that the mechanisms that lead to protein misfolding may be shared across neurodegenerative processes, suggesting a common underlying pathology. Main body This review discusses the literature to date of the shared features of protein misfolding, failures in proteostasis, and potential propagation pathways across the main neurodegenerative disorders. Conclusion The current data suggests, despite overarching processes being shared, that the molecular events implicated in protein pathology are distinct across common neurodegenerative disorders.

scholarly journals Engineering therapeutic protein disaggregases

2016 ◽  
Vol 27 (10) ◽  
pp. 1556-1560 ◽  
Author(s):  
James Shorter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Therapeutic Agents ◽  
Loss Of Function ◽  
Native Structure ◽  
Aaa Atpase ◽  
Protein Misfolding And Aggregation ◽  
Small Molecule Enhancers ◽  
Lateral Sclerosis

Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD.

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