ChemInform Abstract: Modulating Self-Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms

The term “amyloid” refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g., by proteolysis. Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly, leading to insoluble oligomers and lastly to fibrils. These highly ordered protein aggregates have been, for a long time, mainly associated with human neurodegenerative diseases such as Alzheimer’s disease (Amyloid-β peptides). However, they also exert physiological functions such as in release of deposited hormones in human beings. In the light of the rediscovery of our microbial commensals as important companions in health and disease, the fact that microbes also possess amyloidogenic peptides is intriguing. Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact. What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids? Moreover, as the microbial amyloids are evolutionarily older, we might learn from these organisms how to cope with the sword of Damocles forged of endogenous, potentially toxic peptides. This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids.

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Using Molecular Tweezers to Remodel Abnormal Protein Self-Assembly and Inhibit the Toxicity of Amyloidogenic Proteins

Methods in Molecular Biology - Peptide Self-Assembly ◽

10.1007/978-1-4939-7811-3_24 ◽

2018 ◽

pp. 369-386 ◽

Cited By ~ 4

Author(s):

Ravinder Malik ◽

Jing Di ◽

Gayatri Nair ◽

Aida Attar ◽

Karen Taylor ◽

...

Keyword(s):

Self Assembly ◽

Molecular Tweezers ◽

Abnormal Protein ◽

Amyloidogenic Proteins

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Stem Cell-Derived Exosomes as Therapeutic Approach for Neurodegenerative Disorders: From Biology to Biotechnology

Cells ◽

10.3390/cells9122663 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2663

Author(s):

Rodrigo Pinheiro Araldi ◽

Fernanda D’Amelio ◽

Hugo Vigerelli ◽

Thatiana Correa de Melo ◽

Irina Kerkis

Keyword(s):

Stem Cell ◽

Cell Therapy ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Therapeutic Approach ◽

Rapid Rise ◽

Cell Based Therapy ◽

New Treatments ◽

Medical Advances ◽

Minimal Information

The aging population has contributed to the rapid rise in the global incidence of neurodegenerative diseases. Despite the medical advances, there are no effective treatments for these disorders. Therefore, there is an urgent need for new treatments for these diseases. In this sense, cell therapy has been recognized as the best candidate for treating incurable diseases, such as neurodegenerative disorders. However, the therapeutic use of these cells can be limited by several factors. Thus, there has been a rediscovery that extracellular vesicles, including exosomes, can be alternatively explored in the treatment of these diseases, overcoming the limits of cell-based therapy. In this sense, this review aims to revisit all areas from biology, including biogenesis and the content of exosomes, to biotechnology, proposing the minimal information required to isolate, characterize, and study the content of these vesicles for scientific and/or clinical purposes.

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Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001602 ◽

2010 ◽

Vol 12 ◽

Cited By ~ 112

Author(s):

Jacques Fantini ◽

Nouara Yahi

Keyword(s):

Neurodegenerative Diseases ◽

Conformational Changes ◽

Amyloid Fibrils ◽

Fine Tuning ◽

Neural Cells ◽

Amyloidogenic Proteins ◽

Innovative Therapies ◽

Conformational Plasticity ◽

Direct Binding ◽

Α Helix

Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.

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Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

International Journal of Molecular Sciences ◽

10.3390/ijms19082449 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2449 ◽

Cited By ~ 8

Author(s):

Yutaka Sadakane ◽

Masahiro Kawahara

Keyword(s):

Conformational Changes ◽

Posttranslational Modifications ◽

Self Assembly ◽

Metal Binding ◽

Prion Diseases ◽

Amyloid Formation ◽

Amyloidogenic Proteins ◽

Two Factors ◽

Asparagine Deamidation ◽

Β Amyloid

Increasing evidence suggests that amyloid formation, i.e., self-assembly of proteins and the resulting conformational changes, is linked with the pathogenesis of various neurodegenerative disorders such as Alzheimer’s disease, prion diseases, and Lewy body diseases. Among the factors that accelerate or inhibit oligomerization, we focus here on two non-genetic and common characteristics of many amyloidogenic proteins: metal binding and asparagine deamidation. Both reflect the aging process and occur in most amyloidogenic proteins. All of the amyloidogenic proteins, such as Alzheimer’s β-amyloid protein, prion protein, and α-synuclein, are metal-binding proteins and are involved in the regulation of metal homeostasis. It is widely accepted that these proteins are susceptible to non-enzymatic posttranslational modifications, and many asparagine residues of these proteins are deamidated. Moreover, these two factors can combine because asparagine residues can bind metals. We review the current understanding of these two common properties and their implications in the pathogenesis of these neurodegenerative diseases.

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Amyloids: Regulators of Metal Homeostasis in the Synapse

Molecules ◽

10.3390/molecules25061441 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1441 ◽

Cited By ~ 5

Author(s):

Masahiro Kawahara ◽

Midori Kato-Negishi ◽

Ken-ichiro Tanaka

Keyword(s):

Neurodegenerative Diseases ◽

Conformational Changes ◽

Critical Role ◽

Lewy Body Disease ◽

Metal Homeostasis ◽

Amyloidogenic Proteins ◽

Neurodegenerative Process ◽

Amyloid Oligomers ◽

Associated Proteins ◽

Regulatory Functions

Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

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