Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Mamsa, Somayra; Meloni, Bruno P.

doi:10.3389/fnmol.2021.759729

Cited by 30 publications

(23 citation statements)

References 194 publications

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“…Moreover, the SARS-CoV-2 arginine motif activates TMEM16F, a physiological placental fusogen that was implicated in the aberrant glial phagocytosis of neurons and synapses, emphasizing a novel arginine-linked neurodegeneration mechanism ( Lin et al., 2021 ). Furthermore, as arginine-rich peptides were reported to induce cytotoxicity in AD, viral arginine may be the missing link between cell-cell fusion and neurodegenerative disorders ( Mamsa and Meloni, 2021 ).…”

Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…One of the most commonly used excipients to suppress protein aggregation is L-arginine [ 7 , 8 , 9 , 10 , 11 , 12 ]. Even though the mechanism of the beneficial effect of arginine is still not completely understood, several experimental and theoretical studies have been conducted to elucidate its role.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Arginine on the Phase Stability of Aqueous Hen Egg-White Lysozyme Solutions

Brudar

Hribar-Lee

2023

IJMS

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The effect of arginine on the phase stability of the hen egg-white lysozyme (HEWL) has been studied via molecular dynamics computer simulations, as well as experimentally via cloud-point temperature determination. The experiments show that the addition of arginine increases the stability of the HEWL solutions. The computer simulation results indicate that arginine molecules tend to self-associate. If arginine residues are located on the protein surface, the free arginine molecules stay in their vicinity and prevent the way protein molecules “connect” through them to form clusters. The results are not sensitive to a particular force field and suggest a possible microscopic mechanism of the stabilizing role of arginine as an excipient.

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“…Already in 2017, Nadimidla and colleagues found that poly-L arginine hydrochloride inhibited aggregation of PHF6 and a PHF6* containing fragment as well as of Tau mutant protein P301L (Nadimidla et al 2017). The impact of arginines and arginine-rich peptides is very interesting and was reviewed by Mamsa and Meloni in 2021 in detail (Mamsa and Meloni 2021).…”

Section: Discussionmentioning

confidence: 99%

Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease

Aillaud

Funke

2022

Cell Mol Neurobiol

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Alzheimer disease (AD) is the most common progressive neurodegenerative disorder. AD causes enormous personal and economic burden to society as currently only limited palliative therapeutic options are available. The pathological hallmarks of the disease are extracellular plaques, composed of fibrillar amyloid-β (Aβ), and neurofibrillary tangles inside neurons, composed of Tau protein. Until recently, the search for AD therapeutics was focussed more on the Aβ peptide and its pathology, but the results were unsatisfying. As an alternative, Tau might be a promising therapeutic target as its pathology is closely correlated to clinical symptoms. In addition, pathological Tau aggregation occurs in a large group of diseases, called Tauopathies, and in most of them Aβ aggregation does not play a role in disease pathogenesis. The formation of Tau aggregates is triggered by two hexapeptide motifs within Tau; PHF6* and PHF6. Both fragments are interesting targets for the development of Tau aggregation inhibitors (TAI). Peptides represent a unique class of pharmaceutical compounds and are reasonable alternatives to chemical substances or antibodies. They are attributed with high biological activity, valuable specificity and low toxicity, and often are developed as drug candidates to interrupt protein–protein interactions. The preparation of peptides is simple, controllable and the peptides can be easily modified. However, their application may also have disadvantages. Currently, a few peptide compounds acting as TAI are described in the literature, most of them developed by structure-based design or phage display. Here, we review the current state of research in this promising field of AD therapy development. Graphical Abstract

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Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Cited by 30 publications

References 194 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

The Effect of Arginine on the Phase Stability of Aqueous Hen Egg-White Lysozyme Solutions

Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease

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