Identification of a polyglutamine protein aggregation inhibitor QAI1 and its therapeutic effects on polyglutamine neurodegenerative diseases.

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

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The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab029 ◽

2021 ◽

Author(s):

Benjamin C Creekmore ◽

Yi-Wei Chang ◽

Edward B Lee

Keyword(s):

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Electron Tomography ◽

Ubiquitin Proteasome System ◽

26S Proteasome ◽

X Ray Crystallography ◽

New Information ◽

A Cell ◽

Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

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Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽

10.3390/cells9010075 ◽

2019 ◽

Vol 9 (1) ◽

pp. 75 ◽

Cited By ~ 3

Author(s):

Nicoletta Nuzziello ◽

Loredana Ciaccia ◽

Maria Liguori

Keyword(s):

Neurodegenerative Diseases ◽

Precision Medicine ◽

Target Genes ◽

Drug Disposition ◽

Therapeutic Potential ◽

Response To Treatment ◽

Therapeutic Effects ◽

Exciting Potential ◽

The Central Nervous System ◽

Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

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Developments and new vistas in the field of melanocortins

BioMolecular Concepts ◽

10.1515/bmc-2015-0023 ◽

2015 ◽

Vol 6 (5-6) ◽

pp. 361-382 ◽

Cited By ~ 4

Author(s):

Sheila Leone ◽

Giorgio Noera ◽

Alfio Bertolini

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Sexual Activity ◽

Ischemia Reperfusion ◽

Gouty Arthritis ◽

Traumatic Injury ◽

Large Body ◽

Hypovolemic Shock ◽

Therapeutic Effects ◽

Tissue Ischemia

AbstractMelanocortins play a fundamental role in several basic functions of the organism (sexual activity, feeding, inflammation and immune responses, pain sensitivity, response to stressful situations, motivation, attention, learning, and memory). Moreover, a large body of animal data, some of which were also confirmed in humans, unequivocally show that melanocortins also have impressive therapeutic effects in several pathological conditions that are the leading cause of mortality and disability worldwide (hemorrhagic, or anyway hypovolemic, shock; septic shock; respiratory arrest; cardiac arrest; ischemia- and ischemia/reperfusion-induced damage of the brain, heart, intestine, and other organs; traumatic injury of brain, spinal cord, and peripheral nerves; neuropathic pain; toxic neuropathies; gouty arthritis; etc.). Recent data obtained in animal models seem to moreover confirm previous hypotheses and preliminary data concerning the neurotrophic activity of melanocortins in neurodegenerative diseases, in particular Alzheimer’s disease. Our aim was (i) to critically reconsider the established extrahormonal effects of melanocortins (on sexual activity, feeding, inflammation, tissue hypoperfusion, and traumatic damage of central and peripheral nervous system) at the light of recent findings, (ii) to review the most recent advancements, particularly on the effects of melanocortins in models of neurodegenerative diseases, (iii) to discuss the reasons that support the introduction into clinical practice of melanocortins as life-saving agents in shock conditions and that suggest to verify in clinical setting the impressive results steadily obtained with melanocortins in different animal models of tissue ischemia and ischemia/reperfusion, and finally, (iv) to mention the advisable developments, particularly in terms of selectivity of action and of effects.

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Catalysis of Hydrazone and Oxime Peptide Ligation by Arginine

10.26434/chemrxiv.12988364.v2 ◽

2020 ◽

Author(s):

Nathalie Ollivier ◽

Vangelis Agouridas ◽

Benoît Snella ◽

Rémi Desmet ◽

Hervé Drobecq ◽

...

Keyword(s):

Protein Aggregation ◽

Phosphate Buffer ◽

Side Chain ◽

Neutral Ph ◽

Arginine Hydrochloride ◽

Guanidinium Group ◽

Aggregation Inhibitor ◽

Peptide Ligation

Hydrazone and oxime peptide ligations are catalyzed by arginine. The catalysis is assisted intramolecularly by the side-chain guanidinium group. Hydrazone ligation in the presence of arginine proceeds efficiently in phosphate buffer at neutral pH but is particularly powerful in bicarbonate/CO<sub>2</sub> buffer. In addition to acting as a catalyst, arginine prevents the aggregation of proteins during ligation. With its dual properties as nucleophilic catalyst and protein aggregation inhibitor, arginine hydrochloride is a useful addition to the hydrazone/oxime ligation toolbox.<br>

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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity

Journal of Biological Chemistry ◽

10.1074/jbc.m706620200 ◽

2008 ◽

Vol 283 (12) ◽

pp. 7648-7656 ◽

Cited By ~ 64

Author(s):

Amit Mishra ◽

Priyanka Dikshit ◽

Sudarshana Purkayastha ◽

Jaiprakash Sharma ◽

Nobuyuki Nukina ◽

...

Keyword(s):

Protein Aggregation ◽

Proteasomal Degradation ◽

Polyglutamine Protein

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P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21155485 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5485

Author(s):

Ursula A. Germann ◽

John J. Alam

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Therapeutic Target ◽

Kinase Inhibitors ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Therapeutic Effects ◽

P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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Bioactive Profile of Various Salvia officinalis L. Preparations

Plants ◽

10.3390/plants8030055 ◽

2019 ◽

Vol 8 (3) ◽

pp. 55 ◽

Cited By ~ 12

Author(s):

Martina Jakovljević ◽

Stela Jokić ◽

Maja Molnar ◽

Midhat Jašić ◽

Jurislav Babić ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Traditional Medicine ◽

Salvia Officinalis ◽

Therapeutic Effects ◽

Extraction Techniques ◽

Beneficial Effects ◽

Research Findings ◽

Extraction Parameters ◽

Salvia Officinalis L ◽

Polyphenol Profile

Salvia officinalis L., also known as the “Salvation Plant”, has been long used and well-documented in traditional medicine around the globe. Its bioactive compounds, and especially its polyphenol profile, have been extensively researched and reviewed. However, sage’s beneficial effects reach much further, and nowadays, with a range of new extraction techniques, we are discovering new components with new therapeutic effects, especially in the context of neurodegenerative diseases and various carcinomas. This review describes the bioactive profile of various sage preparations depending on the extraction techniques and extraction parameters, and this review lists the newest research findings on its health effects.

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