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Cells
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Calpains in Health and Diseases
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Calpains in Health and Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 July 2021) | Viewed by 13837

Special Issue Editors

Dr. Huu Phuc Nguyen

E-Mail Website
Guest Editor
Department of Human Genetics, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany
Interests: polyglutamine disorders; neurodegenerative diseases; huntington disease; spinocerebellar ataxias; transgenic animal models; gene therapy; regenerative medicine; calpains; neurogenetics
Special Issues, Collections and Topics in MDPI journals
Dr. Jonasz Jeremiasz Weber

E-Mail Website
Assistant Guest Editor
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72074 Tübingen, Germany
Interests: polyglutamine disorders; huntington disease; spinocerebellar ataxia type 3; toxic fragment hypothesis; proteolytic cleavage; degradomics; calpains

Special Issue Information

Dear Colleagues,

Amongst the diversity of proteolytic machinery within cells, calpains constitute some of the few known proteases, whose activation is directly dependent on intracellular calcium ions. Together with the calpain small regulatory subunit 1 and the endogenous proteinaceous inhibitor calpastatin, they form the calpain system, an important modulator of a wide range of cellular functions. Disturbances of the calpain system—as triggered by mutations of calpain genes or the disruption of calcium homeostasis—are implicated in multiple medical conditions, including neurodegenerative diseases, cardiovascular disorders, myopathies, ophthalmic diseases, and cancer. Intriguingly, a whole class of disorders termed calpainopathies are caused by mutations in calpain genes, underscoring the significance of these proteases. Although more than fifty years have passed since the discovery of the first calpains and great efforts have been made to understand the exact role of these enzymes, knowledge about them remains fragmented. This Special Issue will cover the current research and research perspectives on calpains in health and disease, and elucidate the potential of targeting the calpain system as a unifying therapeutic strategy. We welcome relevant research and review articles that will help us piece together the complex calpain puzzle and inspire scientists to further scrutinize this fascinating class of proteases.

Dr. Huu Phuc Nguyen
Dr. Jonasz Jeremiasz Weber
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. Cells 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

  • calpains
  • proteolytic cleavage
  • calpain activation
  • toxic protein fragments
  • calcium homeostasis and dyshomeostasis
  • calpain inhibitors
  • calpastatin
  • calpain reporters

Published Papers (3 papers)

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Research

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15 pages, 1316 KiB  
Article
A Novel Calpain Inhibitor Compound Has Protective Effects on a Zebrafish Model of Spinocerebellar Ataxia Type 3
by Katherine J. Robinson, Kristy Yuan, Stuart K. Plenderleith, Maxinne Watchon and Angela S. Laird
Cells 2021, 10(10), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102592 - 29 Sep 2021
Cited by 7 | Viewed by 4311
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the human ATXN3 gene containing an expanded CAG repeat region, encoding a human ataxin-3 protein with a long polyglutamine (polyQ) repeat region. Previous studies have demonstrated [...] Read more.
Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the human ATXN3 gene containing an expanded CAG repeat region, encoding a human ataxin-3 protein with a long polyglutamine (polyQ) repeat region. Previous studies have demonstrated that ataxin-3 containing a long polyQ length is highly aggregation prone. Cleavage of the ataxin-3 protein by calpain proteases has been demonstrated to be enhanced in SCA3 models, leading to an increase in the aggregation propensity of the protein. Here, we tested the therapeutic potential of a novel calpain inhibitor BLD-2736 for the treatment of SCA3 by testing its efficacy on a transgenic zebrafish model of SCA3. We found that treatment with BLD-2736 from 1 to 6 days post-fertilisation (dpf) improves the swimming of SCA3 zebrafish larvae and decreases the presence of insoluble protein aggregates. Furthermore, delaying the commencement of treatment with BLD-2736, until a timepoint when protein aggregates were already known to be present in the zebrafish larvae, was still successful at removing enhanced green fluorescent protein (EGFP) fused-ataxin-3 aggregates and improving the zebrafish swimming. Finally, we demonstrate that treatment with BLD-2736 increased the synthesis of LC3II, increasing the activity of the autophagy protein quality control pathway. Together, these findings suggest that BLD-2736 warrants further investigation as a treatment for SCA3 and related neurodegenerative diseases. Full article
(This article belongs to the Special Issue Calpains in Health and Diseases)
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Review

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11 pages, 967 KiB  
Review
The Diverse Calpain Family in Trypanosomatidae: Functional Proteins Devoid of Proteolytic Activity?
by Vítor Ennes-Vidal, Marta Helena Branquinha, André Luis Souza dos Santos and Claudia Masini d’Avila-Levy
Cells 2021, 10(2), 299; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020299 - 01 Feb 2021
Cited by 5 | Viewed by 2458
Abstract
Calpains are calcium-dependent cysteine peptidases that were originally described in mammals and, thereafter, their homologues were identified in almost all known living organisms. The deregulated activity of these peptidases is associated with several pathologies and, consequently, huge efforts have been made to identify [...] Read more.
Calpains are calcium-dependent cysteine peptidases that were originally described in mammals and, thereafter, their homologues were identified in almost all known living organisms. The deregulated activity of these peptidases is associated with several pathologies and, consequently, huge efforts have been made to identify selective inhibitors. Trypanosomatids, responsible for life-threatening human diseases, possess a large and diverse family of calpain sequences in their genomes. Considering that the current therapy to treat trypanosomatid diseases is limited to a handful of drugs that suffer from unacceptable toxicity, tough administration routes, like parenteral, and increasing treatment failures, a repurposed approach with calpain inhibitors could be a shortcut to successful chemotherapy. However, there is a general lack of knowledge about calpain functions in these parasites and, currently, the proteolytic activity of these proteins is still an open question. Here, we highlight the current research and perspectives on trypanosomatid calpains, overview calpain description in these organisms, and explore the potential of targeting the calpain system as a therapeutic strategy. This review gathers the current knowledge about this fascinating family of peptidases as well as insights into the puzzle: are we unable to measure calpain activity in trypanosomatids, or are the functions of these proteins devoid of proteolytic activity in these parasites? Full article
(This article belongs to the Special Issue Calpains in Health and Diseases)
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16 pages, 3330 KiB  
Review
Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death
by Yubin Wang, Yan Liu, Xiaoning Bi and Michel Baudry
Cells 2020, 9(12), 2698; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122698 - 16 Dec 2020
Cited by 30 | Viewed by 6060
Abstract
Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years [...] Read more.
Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions. Full article
(This article belongs to the Special Issue Calpains in Health and Diseases)
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