Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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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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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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Prion-Like Proteins in Phase Separation and Their Link to Disease

Biomolecules ◽

10.3390/biom11071014 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1014

Author(s):

Macy L. Sprunger ◽

Meredith E. Jackrel

Keyword(s):

Protein Folding ◽

Phase Transitions ◽

Phase Separation ◽

Liquid Phase ◽

Protein Misfolding ◽

Solid Phase ◽

Liquid Phase Separation ◽

Therapeutic Approaches ◽

Important Physiological Process ◽

Liquid Liquid Phase Separation

Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions.

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Protein misfolding in neurodegenerative diseases: implications and strategies

Translational Neurodegeneration ◽

10.1186/s40035-017-0077-5 ◽

2017 ◽

Vol 6 (1) ◽

Cited By ~ 184

Author(s):

Patrick Sweeney ◽

Hyunsun Park ◽

Marc Baumann ◽

John Dunlop ◽

Judith Frydman ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding

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Multitarget therapeutic approaches for Alzheimer's and Parkinson's diseases: an opportunity or an illusion?

Future Medicinal Chemistry ◽

10.4155/fmc-2021-0119 ◽

2021 ◽

Author(s):

Maria João Matos

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Therapeutic Options ◽

Therapeutic Approaches ◽

Recent Information ◽

Temporary Relief ◽

Parkinson’S Diseases ◽

Innovative Approaches

Alzheimer's and Parkinson's disease are the most prevalent neurodegenerative diseases and the leading causes of dementia worldwide. The etiology of these multifactorial pathologies is not completely known. The available therapeutic approaches can cause temporary relief of symptoms but cannot slow down their progression or cure them. Life-changing therapeutic solutions are urgently needed, as the number of people suffering from these pathologies has been increasing quickly over the last few decades. Several targets are being studied, and innovative approaches are being pursued to find new therapeutic options. This overview is focused on the most recent information regarding the paradigm of using multitarget compounds to treat both Alzheimer's and Parkinson's disease.

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Prionopathies and Prionlike Protein Aberrations in Neurodegenerative Diseases

Neurographics ◽

10.3174/ng.2000035 ◽

2021 ◽

Vol 11 (2) ◽

pp. 127-148

Author(s):

K.N. Anderson ◽

W.B. Overcast ◽

J.R. Brosch ◽

B.D. Graner ◽

M.C. Veronesi

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Clinical Presentation ◽

Prion Diseases ◽

Imaging Biomarkers ◽

Amyloid Pet ◽

Imaging Features ◽

Jakob Disease ◽

The Common ◽

Neuro Imaging

Protein misfolding has been an area of intense research and is implicated in a number of neurodegenerative diseases. Key proteins in the brain lose their native ability to fold and instead assume abnormal conformations. Misfolded proteins cluster to form pathologic aggregates, which cause cellular dysfunction, neuronal death, and neurodegeneration. The prionopathies are best known among the neurodegenerative diseases for their ability to misfold, self-propagate, and infect other organisms. There is increasing evidence of a rationale for a prionlike mechanism of spread of other neurodegenerative diseases through a similar seeding mechanism. In this review, we detail the role of a key protein aberration known to the various prion diseases, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; variably protease-sensitive prionopathy; Gerstmann-Straussler-Scheinker disease; fatal familial insomnia; and kuru. We also discuss the clinical presentation, the available, and emerging imaging options for these diseases. In the second part of this review, we delineate how a prionlike seeding process may be driving the progression of other neurodegenerative diseases, including Parkinson disease, Alzheimer disease, and Huntington disease. A discussion of clinical presentation and imaging features of these example diseases follows to make a case for a common approach to developing imaging biomarkers and therapies of these diseases.Learning Objective: Upon completion of this article, one should be able to describe the various types of prion diseases, recognize and identify the common the neuro-imaging findings in prion diseases, describe seeding mechanism of prion disease, list the common amyloid PET tracers used for Alzheimer’s disease, and list common imaging biomarkers in neurodegenerative diseases.

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Guarana (Paullinia cupana) Extract Protects Caenorhabditis elegans Models for Alzheimer Disease and Huntington Disease through Activation of Antioxidant and Protein Degradation Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9241308 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 15

Author(s):

Patrícia Ferreira Boasquívis ◽

Giovanna Melo Martins Silva ◽

Franciny Aparecida Paiva ◽

Rodrigo Marinho Cavalcanti ◽

Cecília Verônica Nunez ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Protein Misfolding ◽

Therapeutic Potential ◽

High Energy ◽

Protective Effects ◽

Independent Manner ◽

Paullinia Cupana ◽

Age Related ◽

Polyq Protein ◽

Underlying Mechanisms

Guarana (Paullinia cupana) is largely consumed in Brazil in high energy drinks and dietary supplements because of its stimulant activity on the central nervous system. Although previous studies have indicated that guarana has some protective effects in Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) disease models, the underlying mechanisms are unknown. Here, we investigated the protective effects of guarana hydroalcoholic extract (GHE) in Caenorhabditis elegans models of HD and AD. GHE reduced polyglutamine (polyQ) protein aggregation in the muscle and also reduced polyQ-mediated neuronal death in ASH sensory neurons and delayed β-amyloid-induced paralysis in a caffeine-independent manner. Moreover, GHE’s protective effects were not mediated by caloric restriction, antimicrobial effects, or development and reproduction impairment. Inactivation of the transcription factors SKN-1 and DAF-16 by RNAi partially blocked the protective effects of GHE treatment in the AD model. We show that the protective effect of GHE is associated with antioxidant activity and modulation of proteostasis, since it increased the lifespan and proteasome activity, reduced intracellular ROS and the accumulation of autophagosomes, and increased the expression of SOD-3 and HSP-16.2. Our findings suggest that GHE has therapeutic potential in combating age-related diseases associated with protein misfolding and accumulation.

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