Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases

Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

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Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

Current Pharmaceutical Design ◽

10.2174/1381612825666190829151314 ◽

2019 ◽

Vol 25 (28) ◽

pp. 3057-3073 ◽

Cited By ~ 6

Author(s):

Kobra B. Juybari ◽

Azam Hosseinzadeh ◽

Habib Ghaznavi ◽

Mahboobeh Kamali ◽

Ahad Sedaghat ◽

...

Keyword(s):

Optic Nerve ◽

Mitochondrial Dysfunction ◽

Signaling Pathways ◽

Retinal Ganglion Cells ◽

Molecular Mechanisms ◽

Nitrosative Stress ◽

Ganglion Cells ◽

Axon Growth ◽

Nerve Fibers ◽

Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

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

Current Protein and Peptide Science ◽

10.2174/1389203721999201208200605 ◽

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.

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Conformation as the Therapeutic Target for Neurodegenerative Diseases

Current Alzheimer Research ◽

10.2174/1567205014666170116152622 ◽

2017 ◽

Vol 14 (4) ◽

pp. 393-402 ◽

Cited By ~ 6

Author(s):

Rajaraman Krishnan ◽

Franz Hefti ◽

Haim Tsubery ◽

Michal Lulu ◽

Ming Proschitsky ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Specific Binding ◽

Drug Candidate ◽

High Affinity ◽

Novel Approach ◽

Multiple Protein ◽

Clinical Benefits ◽

Effective Drugs

Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.

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Neurodegenerative disorders associated with genes of mitochondria

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00215-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vaibhav S. Marde ◽

Prerna L. Tiwari ◽

Nitu L. Wankhede ◽

Brijesh G. Taksande ◽

Aman B. Upaganlawar ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorders ◽

Friedreich Ataxia ◽

Mitochondrial Genes ◽

Disease Development ◽

Main Text ◽

Functional Studies ◽

Dominant Part ◽

Causative Link

Abstract Background Over the last decade, aggregating evidences suggested that there is a causative link between mutation in gene associated with mitochondrial dysfunction and development of several neurodegenerative disorders. Main text Recent structural and functional studies associated with mitochondrial genes have shown that mitochondrial abnormalities possibly lead to mitochondrial dysfunction. Several studies on animal models of neurodegenerative diseases and mitochondrial genes have provided compelling evidence that mitochondria is involved in the initiation as well as progression of diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and Friedreich ataxia (FA). Conclusion In this mini-review, we have discussed the different etiologic and pathogenesis connected with the mitochondrial dysfunction and relevant neurodegenerative diseases that underlie the dominant part of mitochondrial genes in the disease development and its progress.

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The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22020934 ◽

2021 ◽

Vol 22 (2) ◽

pp. 934

Author(s):

Woon-Man Kung ◽

Muh-Shi Lin

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Management Strategies ◽

Nuclear Factor Κb ◽

Peroxisome Proliferator ◽

Proinflammatory Response ◽

Pharmacological Management ◽

Peroxisome Proliferator Activated Receptor ◽

Iron Sulfur ◽

Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

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