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Protein Folding, Misfolding, and Age-Related Disease
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Protein Folding, Misfolding, and Age-Related Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 3478

Special Issue Editor

Dr. Srinivas Ayyadevara

E-Mail Website
Guest Editor
1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2. Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Interests: Alzheimer’s disease; aging; determinants of longevity; neurodegenerative diseases; cardiovascular disease; cachexia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein homeostasis failure has been implicated in a variety of age-associated disorders, in particular, neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, which are clinically diagnosed by the accumulation of disease-specific aggregates. Such foci reflect the net balance of aggregate accrual and clearance, and both aggregate number and size are correlated with pathological declines in physiological function. Protein misfolding may occur during translation or may arise later due to protein oxidation or modification. Interventions that reduce protein aggregation may help to preserve normal physiology. This Special Issue aims to bring together research and review articles on molecular aspects of protein folding and misfolding. It also seeks to highlight new discoveries, approaches, and technical developments in research on protein folding and homeostasis. By providing an open platform for sharing original research addressing molecular aspects of protein folding and misfolding, we hope to advance our understanding of their roles in aging and age-associated diseases and to facilitate the development of novel diagnostic and therapeutic approaches.

Topics of this Special Issue include but are not limited to:

  • Protein aggregation;
  • Protein aggregation biomarkers: screening, diagnosis, treatment response, and prognosis;
  • Key biological processes that alter protein folding such as chaperones, stress, inflammation, or changes in autophagy and ubiquitin/proteasomal pathways;
  • Bioinformatic approaches to understanding the protein folding process;
  • Small molecule development and intervention to prevent or reverse protein misfolding and aggregation;
  • Contribution of disordered proteins to protein homeostasis.

Dr. Srinivas Ayyadevara
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • protein folding
  • chaperone
  • aging
  • protein misfolding and aggregation
  • age-related disease
  • neurodegeneration

Published Papers (2 papers)

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Research

15 pages, 3734 KiB  
Article
Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases
by Akshatha Ganne, Meenakshisundaram Balasubramaniam, Nirjal Mainali, Paavan Atluri, Robert J. Shmookler Reis and Srinivas Ayyadevara
Int. J. Mol. Sci. 2022, 23(24), 15457; https://doi.org/10.3390/ijms232415457 - 07 Dec 2022
Cited by 4 | Viewed by 1441
Abstract
The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt–Jakob [...] Read more.
The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Age-Related Disease)
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12 pages, 2613 KiB  
Article
Folding Mechanism and Aggregation Propensity of the KH0 Domain of FMRP and Its R138Q Pathological Variant
by Daniele Santorelli, Francesca Troilo, Francesca Fata, Francesco Angelucci, Nicola Demitri, Giorgio Giardina, Luca Federici, Flavia Catalano, Adele Di Matteo and Carlo Travaglini-Allocatelli
Int. J. Mol. Sci. 2022, 23(20), 12178; https://doi.org/10.3390/ijms232012178 - 12 Oct 2022
Cited by 1 | Viewed by 1616
Abstract
The K-homology (KH) domains are small, structurally conserved domains found in proteins of different origins characterized by a central conserved βααβ “core” and a GxxG motif in the loop between the two helices of the KH core. In the eukaryotic KHI type, additional [...] Read more.
The K-homology (KH) domains are small, structurally conserved domains found in proteins of different origins characterized by a central conserved βααβ “core” and a GxxG motif in the loop between the two helices of the KH core. In the eukaryotic KHI type, additional αβ elements decorate the “core” at the C-terminus. Proteins containing KH domains perform different functions and several diseases have been associated with mutations in these domains, including those in the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein crucial for the control of RNA metabolism whose lack or mutations lead to fragile X syndrome (FXS). Among missense mutations, the R138Q substitution is in the KH0 degenerated domain lacking the classical GxxG motif. By combining equilibrium and kinetic experiments, we present a characterization of the folding mechanism of the KH0 domain from the FMRP wild-type and of the R138Q variant showing that in both cases the folding mechanism implies the accumulation of an on-pathway transient intermediate. Moreover, by exploiting a battery of biophysical techniques, we show that the KH0 domain has the propensity to form amyloid-like aggregates in mild conditions in vitro and that the R138Q mutation leads to a general destabilization of the protein and to an increased fibrillogenesis propensity. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Age-Related Disease)
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