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Protein Misfolding in Health and Diseases
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Protein Misfolding in Health and Diseases

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 9490

Special Issue Editor

Prof. Dr. Patrick Lajoie

E-Mail Website
Guest Editor
Department of Anatomy and Cell Biology, University of Western Ontario, London, ON N6A-5C1, Canada
Interests: misfolded protein stress; aging; yeast genetics; Huntington’s disease; proteostasis; fluorescent proteins; unfolded protein response

Special Issue Information

Dear Colleagues,

The ability to fold newly synthetized proteins into their proper conformation is essential to ensure protein function and prevent accumulation of toxic misfolded intermediates. To detect and respond to proteotoxic stress, cells have evolved a plethora of signaling pathways, such as the endoplasmic reticulum unfolded protein response (UPR) and the cytoplasmic heat shock response (HSR) to adapt their folding capacity. Unmitigated proteotoxic stress can often lead to cell death. The ability to monitor and respond to changes in the misfoled protein burden due to environmental and genetics stresses often dictates cell fate. Hence, unmitigated proteotoxic stress is linked to major human disorders, such as (but not limited to) diabetes, cancer, cardiac dysfunctions, and several neurodegenerative diseases, including Huntington’s, Parkinson’s, and Alzheimer’s. The control of stress response pathways via genetic and pharmalogical strategies therefore emerges as a promising therapeutic avenue for protein misfolding diseases.

This Special Issue entitled “Protein Misfolding in Health and Diseases” will focus on how cells and organisms cope with the aberrant accumulation of misfolded proteins and potential therapeutic approaches to protein misfolding diseases. Submissions are encouraged from scientists working on any model organisms. Authors are invited to submit original research and review papers addressing the abovementioned topics of this Special Issue.

Prof. Dr. Patrick Lajoie
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

  • proteins folding
  • misfolded protein stress
  • genetics
  • genomics
  • therapy
  • cell signaling
  • model organisms
  • stress responses
  • unfolded protein response
  • drug discovery
  • protein quality control

Published Papers (3 papers)

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Research

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21 pages, 5442 KiB  
Article
Pathological ATX3 Expression Induces Cell Perturbations in E. coli as Revealed by Biochemical and Biophysical Investigations
by Diletta Ami, Barbara Sciandrone, Paolo Mereghetti, Jacopo Falvo, Tiziano Catelani, Cristina Visentin, Paolo Tortora, Salvador Ventura, Antonino Natalello and Maria Elena Regonesi
Int. J. Mol. Sci. 2021, 22(2), 943; https://doi.org/10.3390/ijms22020943 - 19 Jan 2021
Cited by 6 | Viewed by 2550
Abstract
Amyloid aggregation of human ataxin-3 (ATX3) is responsible for spinocerebellar ataxia type 3, which belongs to the class of polyglutamine neurodegenerative disorders. It is widely accepted that the formation of toxic oligomeric species is primarily involved in the onset of the disease. For [...] Read more.
Amyloid aggregation of human ataxin-3 (ATX3) is responsible for spinocerebellar ataxia type 3, which belongs to the class of polyglutamine neurodegenerative disorders. It is widely accepted that the formation of toxic oligomeric species is primarily involved in the onset of the disease. For this reason, to understand the mechanisms underlying toxicity, we expressed both a physiological (ATX3-Q24) and a pathological ATX3 variant (ATX3-Q55) in a simplified cellular model, Escherichia coli. It has been observed that ATX3-Q55 expression induces a higher reduction of the cell growth compared to ATX3-Q24, due to the bacteriostatic effect of the toxic oligomeric species. Furthermore, the Fourier transform infrared microspectroscopy investigation, supported by multivariate analysis, made it possible to monitor protein aggregation and the induced cell perturbations in intact cells. In particular, it has been found that the toxic oligomeric species associated with the expression of ATX3-Q55 are responsible for the main spectral changes, ascribable mainly to the cell envelope modifications. A structural alteration of the membrane detected through electron microscopy analysis in the strain expressing the pathological form supports the spectroscopic results. Full article
(This article belongs to the Special Issue Protein Misfolding in Health and Diseases)
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18 pages, 9983 KiB  
Article
Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
by Sonja E. Di Gregorio, Kathryn Volkening, Michael J. Strong and Martin L. Duennwald
Int. J. Mol. Sci. 2020, 21(16), 5597; https://doi.org/10.3390/ijms21165597 - 5 Aug 2020
Cited by 7 | Viewed by 3235
Abstract
The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected [...] Read more.
The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF-interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis. Full article
(This article belongs to the Special Issue Protein Misfolding in Health and Diseases)
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Review

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17 pages, 1252 KiB  
Review
The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism
by Shelby L. Oke and Daniel B. Hardy
Int. J. Mol. Sci. 2021, 22(13), 6986; https://doi.org/10.3390/ijms22136986 - 29 Jun 2021
Cited by 17 | Viewed by 3266
Abstract
Disruption of the in utero environment can have dire consequences on fetal growth and development. Intrauterine growth restriction (IUGR) is a pathological condition by which the fetus deviates from its expected growth trajectory, resulting in low birth weight and impaired organ function. The [...] Read more.
Disruption of the in utero environment can have dire consequences on fetal growth and development. Intrauterine growth restriction (IUGR) is a pathological condition by which the fetus deviates from its expected growth trajectory, resulting in low birth weight and impaired organ function. The developmental origins of health and disease (DOHaD) postulates that IUGR has lifelong consequences on offspring well-being, as human studies have established an inverse relationship between birth weight and long-term metabolic health. While these trends are apparent in epidemiological data, animal studies have been essential in defining the molecular mechanisms that contribute to this relationship. One such mechanism is cellular stress, a prominent underlying cause of the metabolic syndrome. As such, this review considers the role of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation in the pathogenesis of metabolic disease in IUGR offspring. In addition, we summarize how uncontrolled cellular stress can lead to programmed cell death within the metabolic organs of IUGR offspring. Full article
(This article belongs to the Special Issue Protein Misfolding in Health and Diseases)
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