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Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 17215

Special Issue Editor

Dr. Aleksandar M. Jeremic

E-Mail Website
Guest Editor
Department of Biological Sciences, The George Washington University, Washington, DC, USA
Interests: islet biology; amyloidosis; β-cell function; protein trafficking and proteotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyloidosis is a biological event in which proteins undergo structural/physical transitions from soluble monomers and oligomers to insoluble beta-sheet enriched fibrillar aggregates. Exactly how and why amyloid proteins aggregate is still not well understood. This Special Issue brings together biochemistry, biophysics, structural/cell biology, and medicine to discuss cutting-edge research on molecular mechanisms and the novel treatments of a broad range of amyloid diseases. We summarize the main mechanisms of (mis)folding, trafficking, and toxicity of amyloid proteins and peptides in eukaryotic cells.

We discuss how a structurally and functionally diverse class of amyloid proteins are recognized and degraded by cells and describe cellular and therapeutic strategies to evade or halt toxic structural protein forms. In addition to exploring the fundamental question of how cells distinguish between toxic and non-toxic amyloid species, we consider the mechanisms of amyloid proteins transport across the cell plasma membrane and their intracellular trafficking and recycling pathways. This issue also examines amyloid proteins folding intermediates and defines the role of membrane cholesterol and lipids in amyloid proteins’ structural conversions; it unravels amino acids and lipids driving amyloid’s structural transitions in solution and on membranes; it investigates internalization, trafficking, and secretory pathways of amyloid proteins and uncovers the roles of amyloid receptors and other signaling molecules in amyloid-induced cellular stress. Finally, the role of various proteolytic systems and amyloid modulators, synthetic and natural, in turnover and toxicity of amyloid proteins is illuminated.

With the aid of biophysical, biochemical, molecular imaging, and genetic approaches, a diverse group of scientists deliberate in this Special Issue the molecular and biochemical events leading to the formation of amyloid oligomers and aggregates or plaques. This knowledge is critical for the development of novel therapeutics for the treatment of metabolic, neurological, and other amyloid-associated disorders.

You may choose our Joint Special Issue in Chemistry.

Dr. Aleksandar M. Jeremic
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Structure and pathophysiology of amyloid proteins
  • Protein oligomerization and aggregation pathways in vitro and in vivo
  • Trafficking, secretory and recycling pathways of amyloid proteins
  • Amyloid receptors and cell signaling
  • Proteotoxicity
  • Proteasome and proteolytic enzymes in amyloid clearance
  • Role of Golgi and other organelles in amyloid formation
  • Small molecules and natural amyloid inhibitors 
  • Amyloid pathology and drug design
  • Computational tools / bioinformatics in understanding amyloidosis

Related Special Issue

Published Papers (5 papers)

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Research

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21 pages, 3361 KiB  
Article
Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis
by Gareth J. Morgan
Molecules 2021, 26(12), 3571; https://doi.org/10.3390/molecules26123571 - 11 Jun 2021
Cited by 9 | Viewed by 2893
Abstract
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps [...] Read more.
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments)
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14 pages, 4176 KiB  
Article
Established Beta Amyloid Pathology Is Unaffected by TREM2 Elevation in Reactive Microglia in an Alzheimer’s Disease Mouse Model
by Qiuju Yuan, Xiaodong Liu, Yi Zhang, Yan-Fang Xian, Juntao Zou, Xie Zhang, Pengyun Huang, You-Qiang Song and Zhi-Xiu Lin
Molecules 2021, 26(9), 2685; https://doi.org/10.3390/molecules26092685 - 4 May 2021
Cited by 1 | Viewed by 2665
Abstract
Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer’s disease (AD). However, findings on the effects of TREM2 on Aβ deposition are quite inconsistent in animal studies, requiring further [...] Read more.
Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer’s disease (AD). However, findings on the effects of TREM2 on Aβ deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aβ pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aβ40 and Aβ42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-β pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aβ pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments)
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Review

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11 pages, 2566 KiB  
Review
Oligomer Formation by Amyloid-β42 in a Membrane-Mimicking Environment in Alzheimer’s Disease
by Terrone L. Rosenberry, Huan-Xiang Zhou, Scott M. Stagg and Anant K. Paravastu
Molecules 2022, 27(24), 8804; https://doi.org/10.3390/molecules27248804 - 12 Dec 2022
Cited by 4 | Viewed by 1850
Abstract
The brains of Alzheimer’s disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by [...] Read more.
The brains of Alzheimer’s disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by two proteases called β-secretase and γ-secretase. Aβ42 differs from Aβ40 in having two additional hydrophobic amino acids, ILE and ALA, at the C-terminus. A small percentage of AD is autosomal dominant (ADAD) and linked either to the genes for the presenilins, which are part of γ-secretase, or APP. Because ADAD shares most pathogenic features with widespread late-onset AD, Aβ peptides have become the focus of AD research. Fibrils formed by the aggregation of these peptides are the major component of plaques and were initially targeted in AD therapy. However, the fact that the abundance of plaques does not correlate well with cognitive decline in AD patients has led investigators to examine smaller Aβ aggregates called oligomers. The low levels and heterogeneity of Aβ oligomers have made the determination of their structures difficult, but recent structure determinations of oligomers either formed or initiated in detergents have been achieved. We report here on the structures of these oligomers and suggest how they may be involved in AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments)
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24 pages, 4091 KiB  
Review
Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas
by Diti Chatterjee Bhowmick, Zhanar Kudaibergenova, Lydia Burnett and Aleksandar M. Jeremic
Molecules 2022, 27(3), 1021; https://doi.org/10.3390/molecules27031021 - 2 Feb 2022
Cited by 14 | Viewed by 5063
Abstract
Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells [...] Read more.
Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP–membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments)
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11 pages, 2251 KiB  
Review
The Ultrastructure of Tissue Damage by Amyloid Fibrils
by Haruki Koike and Masahisa Katsuno
Molecules 2021, 26(15), 4611; https://doi.org/10.3390/molecules26154611 - 29 Jul 2021
Cited by 20 | Viewed by 3837
Abstract
Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue [...] Read more.
Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Turnover and Toxicity of Amyloid Proteins from Cells to Treatments)
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