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Biomolecules
Special Issues
Protein Misfolding Diseases: Molecular Mechanisms and Therapeutic Strategies
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Protein Misfolding Diseases: Molecular Mechanisms and Therapeutic Strategies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Structure and Dynamics".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 1172

Special Issue Editors

Dr. Priyanka Joshi

E-Mail Website
Guest Editor
Georgetown Faculty, Georgetown University, Washington, DC 20057, USA
Interests: protein aggregation; protein misfolding; biomolecular condensation; chemical kinetics; cellular homeostasis; small molecules; antibody therapeutics; drug discovery; neurodegeneration; neurodegenerative diseases
Dr. Michele Perni

E-Mail Website
Guest Editor
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Interests: protein aggregation; protein misfolding; biomolecular condensation; chemical kinetics; cellular homeostasis; small molecules; antibody therapeutics; drug discovery; neurodegeneration; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Misfolded proteins and their isoforms are increasingly being recognized as cytotoxic agents over a wide range of human disorders associated with protein aggregation and biomolecular condensate formation. These disorders, including Alzheimer's and Parkinson's diseases, type II diabetes, and amyotrophic lateral sclerosis, among others, are increasingly prevalent and profoundly debilitating. Recent years have witnessed extensive mechanistic investigations, both in vitro and in vivo, leading to the proposal of various therapeutic strategies. These approaches aim at restoring protein and cellular homeostasis through interventions utilizing natural products, small molecules, antibodies, or human metabolites. This Special Issue will cover some of the most advanced developments in this field, ranging from mechanistic in silico studies, to bench science, method development, and pre-clinical studies.

Dr. Priyanka Joshi
Dr. Michele Perni
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly 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

  • protein aggregation
  • protein misfolding
  • biomolecular condensation
  • chemical kinetics
  • cellular homeostasis
  • small molecules
  • antibody therapeutics
  • drug discovery
  • neurodegeneration
  • neurodegenerative diseases

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Published Papers (1 paper)

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Research

24 pages, 3300 KiB  
Article
α-Synuclein Iron-Responsive-Element RNA and Iron Regulatory Protein Affinity Is Specifically Reduced by Iron in Parkinson’s Disease
by Mateen A. Khan
Biomolecules 2025, 15(2), 214; https://doi.org/10.3390/biom15020214 - 2 Feb 2025
Viewed by 816
Abstract
α-Synuclein (α-Syn) is implicated in the pathophysiology of Parkinson’s disease (PD) and plays a significant role in neuronal degeneration. Iron response proteins (IRPs) bind to iron response elements (IREs) found in the 5′-untranslated regions (5′-UTRs) of the messenger RNA that encode the α-Syn [...] Read more.
α-Synuclein (α-Syn) is implicated in the pathophysiology of Parkinson’s disease (PD) and plays a significant role in neuronal degeneration. Iron response proteins (IRPs) bind to iron response elements (IREs) found in the 5′-untranslated regions (5′-UTRs) of the messenger RNA that encode the α-Syn gene. This study used multi-spectroscopic approach techniques to investigate the impact of iron on α-Syn IRE RNA binding to IRP1. The formation of a stable complex between α-Syn RNA and IRP1 was suggested by fluorescence quenching results. Fluorescence measurements showed that α-Syn RNA and IRP1 had a strong interaction, with a binding constant (Ka) of 21.0 × 106 M−1 and 1:1 binding stoichiometry. About one binding site per IRP1 molecule was suggested by the α-Syn RNA binding. The Ka for α-Syn RNA•IRP1 with added Fe2+ (50 μM) was 6.4 μM−1. When Fe2+ was added, the Ka of α-Syn RNA•IRP1 was reduced by 3.3 times. These acquired Ka values were used to further understand the thermodynamic characteristics of α-Syn RNA•IRP1 interactions. The thermodynamic properties clearly suggested that α-Syn RNA binding to IRP1 was an entropy-favored and enthalpy-driven event, with significant negative ΔH and small positive ΔS. For α-Syn RNA•IRP1, the Gibbs free energy (ΔG) was −43.7 ± 2.7 kJ/mol, but in the presence of Fe2+, it was −36.3 ± 2.1 kJ/mol. These thermodynamic calculations indicated that hydrogen bonding as well as van der Waals interactions might help to stabilize the complex formation. Additionally, far-UV CD spectra verified α-Syn RNA•IRP1 complex formation, and α-Syn RNA and Fe2+ induce secondary structural alteration of IRP1. According to our findings, iron alters the hydrogen bonding in α-Syn RNA•IRP1 complexes and induces a structural change in IRP1. This suggests that iron selectively affects the thermodynamics of these RNA–protein interactions. Full article
(This article belongs to the Special Issue Protein Misfolding Diseases: Molecular Mechanisms and Therapeutic Strategies)
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