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Cells
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Role of Calpains in Health and Diseases
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Role of 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: 30 November 2025 | Viewed by 2857

Special Issue Editors

Dr. Michel Baudry

E-Mail Website
Guest Editor
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA
Interests: mechanisms implicated in long-term synaptic potentiation and depression in hippocampus and other brain regions; regulation of glutamate receptors; role of oxygen free radicals in central nervous system; mechanisms underlying selective neuronal degeneration; computational neuroscience
Dr. Peter A. Greer

E-Mail Website
Guest Editor
Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
Interests: RAF; MEK; inhibits tumorigenesis; breast cancer

Special Issue Information

Dear Colleagues,

Calpains comprise a large family of proteases that are tremendously conserved amongst species and are ubiquitously distributed in tissues. Since their discovery, there has been remarkable progress in understanding their diversity, structure, physiological roles, and involvement in a number of diseases. Today, more than 7,000 research articles focus on the calpains. Because of the increasing relevance of calpains to diseases such as eye diseases, neurodegeneration, muscle and metabolic diseases, wound healing, gastrointestinal disease, inflammation, and cancer, the field is continuously expanding. This Special Issue of Cells will provide the latest findings regarding the mechanisms underlying the roles of calpains in cell functions, the roles of different calpains under physiological and pathological conditions, as well as the translation of these findings into novel therapeutic approaches for several disorders. In addition, genetic studies are indicating that mutations in several calpains play critical roles in the etiology of several diseases, further extending the relevance of calpains in health and diseases.

Dr. Michel Baudry
Dr. Peter A. Greer
Guest Editors

Manuscript Submission Information

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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

  • calpain
  • physiology
  • biochemistry
  • disease
  • mutation
  • target
  • inhibitor

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Published Papers (3 papers)

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Research

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20 pages, 2915 KB  
Article
Neuroprotective Effects of Calpain Inhibition in Parkinson’s Disease: Insights from Cellular and Murine Models
by Vandana Zaman, Amy Gathings, Kelsey P. Drasites, Donald C. Shields, Narendra L. Banik and Azizul Haque
Cells 2025, 14(17), 1310; https://doi.org/10.3390/cells14171310 - 24 Aug 2025
Viewed by 800
Abstract
Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and key pathways such as neuroinflammation, oxidative stress, and autophagy are believed to significantly contribute to the mechanisms of neurodegeneration. Calpain activation plays a critical role in [...] Read more.
Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and key pathways such as neuroinflammation, oxidative stress, and autophagy are believed to significantly contribute to the mechanisms of neurodegeneration. Calpain activation plays a critical role in neuroinflammation and neurodegeneration, as demonstrated by its impact on microglial activation, reactive oxygen species (ROS) production, and neuronal survival. In this study, we investigated the effects of calpain inhibition using calpeptin (CP) and calpain-2-specific inhibitors in cellular and murine models of neuroinflammation and PD. In BV2 microglial cells, LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6) and chemokines (MCP-1, IP-10) were significantly reduced by CP treatment with a concomitant decrease in ROS generation. Similarly, in VSC-4.1 motoneuron cells, calpain inhibition attenuated IFN-γ-induced ROS production and improved cell viability, demonstrating its neuroprotective effects. Moreover, in a murine MPTP model of PD, calpain inhibition reduced astrogliosis, ROCK2 expression, and levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL12p70) and chemokines (MCP-1 and IP-10) in the dorsal striatum and plasma. The specific role of calpain-2 in immune modulation was further highlighted in human microglia, SV-40 cells. With respect to immune modulation in these cells, siRNA-mediated knockdown of calpain-2, but not calpain-1, significantly reduced antigen presentation to CD4+ T cells. Thus, calpain-2 is likely involved in regulating antigen presentation and activation of inflammatory CD4+ T cells. These findings underscore the therapeutic potential of calpain-2 inhibition in mitigating neuroinflammation and neurodegeneration, particularly in PD, by targeting microglial activation, ROS production, and neuronal survival pathways. Full article
(This article belongs to the Special Issue Role of Calpains in Health and Diseases)
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Review

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20 pages, 1149 KB  
Review
Calpain-1 and Calpain-2 in the Brain: What Have We Learned from 45 Years of Research?
by Michel Baudry and Xiaoning Bi
Cells 2025, 14(17), 1301; https://doi.org/10.3390/cells14171301 - 22 Aug 2025
Viewed by 771
Abstract
Although the calcium-dependent proteases, calpains, were discovered more than 60 years ago, we still know very little regarding their functions, mostly because very few studies are addressing questions related to specific members of this relatively large family of cysteine proteases. The “classical calpains”, [...] Read more.
Although the calcium-dependent proteases, calpains, were discovered more than 60 years ago, we still know very little regarding their functions, mostly because very few studies are addressing questions related to specific members of this relatively large family of cysteine proteases. The “classical calpains”, calpain-1 and calpain-2, are ubiquitous and have received more attention because of the special roles they play in the brain. The authors have been studying the properties and functions of these two calpain isoforms in the brain for over 45 years, and this review will focus on what has been learned over this period of time. In particular, we will discuss the numerous studies that have led to the notion that calpain-1 and calpain-2 play opposite functions in the brain on processes ranging from neuronal survival or death, synaptic plasticity, and learning and memory to neurogenesis. Mechanisms underlying these opposite functions are starting to be understood and the findings support the notion that such opposite functions might be a general feature of these two isoforms in any type of cell. This review concludes with a discussion of the potential benefits of selective calpain-2 inhibitors for the treatment of a variety of neurological disorders. Full article
(This article belongs to the Special Issue Role of Calpains in Health and Diseases)
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24 pages, 2999 KB  
Review
Calpain in Traumatic Brain Injury: From Cinderella to Central Player
by Carla Schallerer, Stephan Neuschmid, Barbara E. Ehrlich and Declan McGuone
Cells 2025, 14(16), 1253; https://doi.org/10.3390/cells14161253 - 14 Aug 2025
Viewed by 701
Abstract
Traumatic Brain Injury (TBI) is a major global health concern and a leading cause of death and disability, especially in young adults. It triggers complex secondary injury cascades, e.g., calcium dysregulation, mitochondrial dysfunction and protease activation, that extend well beyond the initial mechanical [...] Read more.
Traumatic Brain Injury (TBI) is a major global health concern and a leading cause of death and disability, especially in young adults. It triggers complex secondary injury cascades, e.g., calcium dysregulation, mitochondrial dysfunction and protease activation, that extend well beyond the initial mechanical insult to drive ongoing neurodegeneration. The calcium-dependent protease calpain has emerged as a central mediator of TBI cellular pathology. Calpain cleaves a broad range of cytoskeletal and regulatory proteins across neuronal compartments, disrupting axonal integrity, synaptic function and calcium homeostasis. Despite decades of research, calpain remains an elusive therapeutic target. In this review, we examine the spatial and temporal patterns of calpain activation in the traumatically injured brain, categorize key calpain substrates by structure and location, and assess their mechanistic roles in TBI pathology. We also review recent advances in next-generation calpain-2 selective inhibitors with enhanced specificity and preclinical efficacy and discuss the emerging use of calpain-cleaved protein fragments such as SBDP145 and SNTF as candidate biomarkers for TBI diagnosis and progression. Drawing on molecular, preclinical, and clinical data, we argue that calpain warrants renewed attention as both a therapeutic target and mechanistic biomarker in TBI. It may be time for Cinderella to leave the basement. Full article
(This article belongs to the Special Issue Role of Calpains in Health and Diseases)
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