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      Development of fluorophores for the detection of oligomeric aggregates of amyloidogenic proteins found in neurodegenerative diseases

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          Abstract

          Alzheimer’s disease and Parkinson’s disease are the two most common neurodegenerative diseases globally. These neurodegenerative diseases have characteristic late-stage symptoms allowing for differential diagnosis; however, they both share the presence of misfolded protein aggregates which appear years before clinical manifestation. Historically, research has focused on the detection of higher-ordered aggregates (or amyloids); however, recent evidence has shown that the oligomeric state of these protein aggregates plays a greater role in disease pathology, resulting in increased efforts to detect oligomers to aid in disease diagnosis. In this review, we summarize some of the exciting new developments towards the development of fluorescent probes that can detect oligomeric aggregates of amyloidogenic proteins present in Alzheimer’s and Parkinson’s disease patients.

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          Most cited references93

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          Alpha-synuclein in Lewy bodies.

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            Cryo-EM structures of Tau filaments from Alzheimer’s disease brain

            Alzheimer’s disease (AD) is the most common neurodegenerative disease, and there are no mechanism-based therapies. AD is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in cerebral cortex. Neurofibrillary lesions are made of paired helical and straight Tau filaments (PHFs and SFs), whereas Tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of Tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of PHFs and SFs from AD brain. Filament cores are made of two identical protofilaments comprising residues 306–378 of Tau, which adopt a combined cross-β/β-helix structure and define the seed for Tau aggregation. PHFs and SFs differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way to study a range of neurodegenerative diseases.
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              Protein misfolding, functional amyloid, and human disease.

              Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2577903/overviewRole: Role: Role:
                URI : https://loop.frontiersin.org/people/2584521/overviewRole: Role:
                URI : https://loop.frontiersin.org/people/2585237/overviewRole: Role: Role: Role:
                Journal
                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                2296-2646
                22 December 2023
                2023
                : 11
                : 1343118
                Affiliations
                Department of Chemistry and Biochemistry , University of California San Diego , San Diego, CA, United States
                Author notes

                Edited by: José Carlos Menéndez, Complutense University of Madrid, Spain

                Reviewed by: Chongzhao Ran, Harvard Medical School, United States

                Álvaro Sarabia Vallejo, Universidad Complutense de Madrid, Spain

                *Correspondence: Jerry Yang, jerryyang@ 123456ucsd.edu
                Article
                1343118
                10.3389/fchem.2023.1343118
                10766704
                38188930
                e72f4d7e-cf92-4b74-8016-990daa6bdc31
                Copyright © 2023 Teppang, Zhao and Yang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 November 2023
                : 11 December 2023
                Funding
                Funded by: National Institute on Aging , doi 10.13039/100000049;
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Institute On Aging of the National Institutes of Health under Award No. 1RF1AG077802.
                Categories
                Chemistry
                Review
                Custom metadata
                Medicinal and Pharmaceutical Chemistry

                fluorescence,probes,proteins,neurodegenerative diseases,oligomers

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