Protein Misfolding in Alzheimer s Disease and Sleep Related Disorders

Heat shock inductors have potential as treatment for degenerative and protein misfolding diseases. Dimethyl-sulfoxide is widely used as a solvent in pharmacological screening tests and has been shown to have heat shock induction effects. Transgenic Tg (hsp70l:EGFP-HRAS_G12V)io3(AB) zebrafish larvae were exposed for 24 hours to dimethyl-sulfoxide in concentratios of 0.1-2%, and to moderate heat shock inductors pentoxifylline and tacrolimus. Positive controls were exposed to 35, 38 and 40�C for 20 min, and incubated for 24 h at 28�C. Heat shock response was measured by fluorescence microscopy and signal intensity quantification in FIJI. Dimethyl-sulfoxide caused a dose-dependant increase in fluorescent intensity, but significantly lower compared with exposure to 38 and 40�C. Pentoxifylline and tacrolimus induced a significantly higher increase in fluorescence compared with 0.5% dimethyl-sulfoxide. Thus, although dimethyl-sulfoxide has independent heat shock induction effects, concentrations of up to 0.5% are suitable for heat shock response screening tests.

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Microbial Genetic Screens for Monitoring Protein Misfolding Associated with Neurodegeneration: Tools for Identifying Disease-Relevant Genes and for Screening Synthetic and Natural Compound Libraries for the Discovery of Potential Therapeutics

Current Pharmaceutical Design ◽

10.2174/1381612824666180515143752 ◽

2018 ◽

Vol 24 (19) ◽

pp. 2055-2075 ◽

Cited By ~ 3

Author(s):

Kalliopi Kostelidou ◽

Ilias Matis ◽

Georgios Skretas

Keyword(s):

Protein Misfolding ◽

Socioeconomic Impact ◽

Genetic Screens ◽

Subsequent Formation ◽

The Past ◽

Compound Libraries ◽

Selection Systems ◽

Cellular Factors ◽

Effective Drugs ◽

Potential Therapeutics

Neurodegenerative Diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of highthroughput assays for the identification of cellular factors and processes that are important mediators of NDassociated proteotoxicities. In addition, such systems have facilitated the discovery of synthetic and natural compounds with the ability to rescue the misfolding and the associated pathogenic effects of aggregation-prone proteins associated with NDs. This review outlines such available systems in bacteria and yeast, whose usage will likely accelerate the pre-clinical discovery process for effective drugs against a variety of NDs with high socioeconomic impact.

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The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

Current Protein and Peptide Science ◽

10.2174/1389203721666200505101734 ◽

2020 ◽

Vol 21 (9) ◽

pp. 846-859

Author(s):

Mohd Saeed ◽

Mohd Adnan Kausar ◽

Rajeev Singh ◽

Arif J. Siddiqui ◽

Asma Akhter

Keyword(s):

Protein Misfolding ◽

Covalent Binding ◽

Critical Role ◽

Enzymatic Reaction ◽

Treatment Strategies ◽

Bioactive Molecules ◽

Carbonyl Stress ◽

Defense System ◽

Pathological Conditions ◽

Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

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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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Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200601161703 ◽

2020 ◽

Vol 20 (26) ◽

pp. 2380-2390 ◽

Cited By ~ 8

Author(s):

Md. Sahab Uddin ◽

Abdullah Al Mamun ◽

Md. Ataur Rahman ◽

Tapan Behl ◽

Asma Perveen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Misfolded Proteins ◽

Cell Organelles ◽

The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

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Autophagy Modulation as a Treatment of Amyloid Diseases

Molecules ◽

10.3390/molecules24183372 ◽

2019 ◽

Vol 24 (18) ◽

pp. 3372 ◽

Cited By ~ 21

Author(s):

Zoe Mputhia ◽

Eugene Hone ◽

Timir Tripathi ◽

Tim Sargeant ◽

Ralph Martins ◽

...

Keyword(s):

Protein Misfolding ◽

Metabolic Diseases ◽

Physiological Role ◽

Cell Loss ◽

Amyloid Proteins ◽

Tissue Degeneration ◽

Polyglutamine Disorders ◽

Amyloid Accumulation ◽

Causative Factors ◽

Amyloid Diseases

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

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Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Biomolecules ◽

10.3390/biom11050767 ◽

2021 ◽

Vol 11 (5) ◽

pp. 767

Author(s):

Priscila Baltazar Gonçalves ◽

Ana Carolina Rennó Sodero ◽

Yraima Cordeiro

Keyword(s):

Drug Discovery ◽

Neurodegenerative Diseases ◽

Green Tea ◽

Protein Misfolding ◽

Financial Burden ◽

Scientific Evidence ◽

Symptomatic Relief ◽

Public Health Problem ◽

Bioactive Compound ◽

Common Cause

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

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Unusual case of amyloidosis presenting as a jejunal mass

BMJ Case Reports ◽

10.1136/bcr-2020-240226 ◽

2021 ◽

Vol 14 (5) ◽

pp. e240226

Author(s):

Sachin Mohan ◽

Elliot Graziano ◽

James Campbell ◽

Irshad H Jafri

Keyword(s):

Small Intestine ◽

Light Chain ◽

Protein Misfolding ◽

Unusual Case ◽

Gi Tract ◽

Organ Systems ◽

Light Chain Disease ◽

Wide Range ◽

Amyloid Light Chain ◽

Possible Cause

Amyloidosis constitutes a heterogeneous group of disorders of protein misfolding that can involve different organ systems. The disease can occur either in a systemic or localised manner that is well known to involve the gastrointestinal (GI) tract. GI amyloidosis can present with a wide range of symptoms including diarrhoea, bleeding and obstruction. This case illustrates a patient with localised jejunal amyloid light chain disease that was diagnosed serendipitously during a workup for haematuria. Our patient was otherwise asymptomatic, but this case underscores the importance of considering amyloidosis as a possible cause of isolated masses of the small intestine.

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