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Molecular Research and Treatment in Multiple Sclerosis

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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 (20 October 2025) | Viewed by 12360

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Special Issue Editors

Dr. Nada Starčević Čizmarević

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Guest Editor

Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
Interests: human genetics; neurodegenerative diseases; multiple sclerosis; cytogenetics

Prof. Dr. Borut Peterlin

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Guest Editor

Clinical Institute of Genomic Medicine, University Medical Center Ljubljana, SI-1000 Ljubljana, Slovenia
Interests: public health genomics; genomic medicine in health systems; mechanisms of human genetic and complex disorders
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Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system with autoimmune and inflammatory features. The precise etiology of MS remains elusive, presumed to result from complex interactions between genetic predispositions and environmental influences, infectious exposures, and factors that lead to pro-inflammatory conditions and neuronal injury. Despite extensive research on the development of new drugs, there is no effective therapy for all patients, and the response of patients to available medication varies greatly.

This Special Issue aims to expand knowledge and clarify the molecular mechanisms and genetic factors involved in multiple sclerosis in order to search for accurate biomarkers and contribute to advances in the treatment of all forms of MS.

This Special Issue only considers papers that use molecular data to improve our understanding of the genetic and molecular basis of the disease and to develop therapeutic strategies based on the underlying mechanisms of MS, neuroprotection, and repair.

Therefore, we invite researchers and clinicians to submit articles with their findings that address various aspects of MS, with a focus on molecular research and treatment strategies.

Dr. Nada Starčević Čizmarević
Dr. Borut Peterlin
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 250 words) can be sent to the Editorial Office for assessment.

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

multiple sclerosis
neuroinflammation
neurodegeneration
genetics
molecular research
biomarkers
neuroimaging
therapy

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Published Papers (5 papers)

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Research

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17 pages, 712 KB

Open AccessArticle

Association of Functional Gene Variants in DYSF–ZNF638, MTSS1 and Ferroptosis-Related Genes with Multiple Sclerosis Severity and Target Gene Expression

by Tamara Djuric, Ana Djordjevic, Jovana Kuveljic, Milan Stefanovic, Evica Dincic, Ana Kolakovic and Maja Zivkovic

Int. J. Mol. Sci. 2025, 26(11), 4986; https://doi.org/10.3390/ijms26114986 - 22 May 2025

Viewed by 1520

Abstract

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan^®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. Full article

(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)

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13 pages, 1742 KB

Open AccessArticle

Progressive Elevation of Store-Operated Calcium Entry-Associated Regulatory Factor (SARAF) and Calcium Pathway Dysregulation in Multiple Sclerosis

by Safa Taha, Muna Aljishi, Ameera Sultan, Moudi E. Al-Nashmi, Moiz Bakhiet, Salvatore Spicuglia and Mohamed Belhocine

Int. J. Mol. Sci. 2025, 26(10), 4520; https://doi.org/10.3390/ijms26104520 - 9 May 2025

Viewed by 1247

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination and neuronal damage in the central nervous system. Dysregulation of calcium homeostasis, particularly through the Store-Operated Calcium Entry-Associated Regulatory Factor (SARAF), has been implicated in MS pathogenesis. This study investigated SARAF, STIM1, and Orai1 expression patterns and their relationship to calcium homeostasis in 45 Bahraini MS patients and 45 matched healthy controls using ELISA and real-time PCR analyses. MS patients showed significantly elevated serum SARAF levels in both early (192.26 ± 47.00 pg/mL) and late MS stages (341.47 ± 96.19 pg/mL) compared to controls (129.82 ± 30.82 pg/mL; p < 0.001. SARAF expressions were markedly increased in MS patients (3.829 ± 0.04422 vs. 1 ± 0; p < 0.0001), while STIM1 (0.4324 ± 0.01471) and ORAI1 (0.2963 ± 0.02156) expressions were significantly reduced compared to the controls (p < 0.0001). Intracellular calcium levels were notably elevated in both early and late MS stages. These findings suggest that the progressive elevation of SARAF, coupled with altered STIM1 and ORAI1 expression, may serve as potential biomarkers for MS progression and represent promising therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)

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19 pages, 2035 KB

Open AccessArticle

MIND Diet Impact on Multiple Sclerosis Patients: Biochemical Changes after Nutritional Intervention

by Ainoa Navarrete-Pérez, Sara Gómez-Melero, Begoña Mª Escribano, Alejandro Galvao-Carmona, Cristina Conde-Gavilán, Mª Ángeles Peña-Toledo, Noelia Villarrubia, Luisa Mª Villar, Isaac Túnez, Eduardo Agüera-Morales and Javier Caballero-Villarraso

Int. J. Mol. Sci. 2024, 25(18), 10009; https://doi.org/10.3390/ijms251810009 - 17 Sep 2024

Cited by 12 | Viewed by 4689

Abstract

There is substantial evidence supporting the neuroprotective effects of the MIND diet in neurodegenerative diseases like Parkinson’s and Alzheimer’s. Our aim was to evaluate the impact of a nutritional intervention (NI) with this diet on multiple sclerosis (MS) patients. The study was conducted in two stages. In the first stage, two groups were included: MS patients before the NI (group A) and healthy control subjects (group B). In this stage, groups (A) and (B) were compared (case–control study). In the second stage, group (A) was assessed after the NI, with comparisons made between baseline and final measurements (before-and-after study). In the case–control stage (baseline evaluation), we found significant differences in fatigue scores (p < 0.001), adherence to the MIND diet (p < 0.001), the serum levels of brain-derived neurotrophic factor (BDNF) (p < 0.001), and higher oxidative status in the MS group, with lower levels of reduced glutathione (p < 0.001), reduced/oxidised glutathione ratio (p < 0.001), and elevated levels of lipoperoxidation (p < 0.002) and 8-hydroxy-2′-deoxyguanosine (p < 0.025). The before-and-after intervention stage showed improvements in fatigue scores (p < 0.001) and physical quality-of-life scores (MSQOL-54) (p < 0.022), along with decreases in the serum levels of glial-derived neurotrophic factor (GDNF) (p < 0.041), lipoperoxidation (p < 0.046), and 8-hydroxy-2′-deoxyguanosine (p < 0.05). Consumption of the MIND diet is linked to clinical and biochemical improvement in MS patients. Full article

(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)

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11 pages, 272 KB

Open AccessArticle

CCR5 Δ32 and CTLA-4 +49 A/G Gene Polymorphisms and Interferon-β Treatment Response in Croatian and Slovenian Multiple Sclerosis Patients

by Jasna Nekić, Ivana Stanković Matić, Valentino Rački, Dolores Janko Labinac, Vladimira Vuletić, Miljenko Kapović, Smiljana Ristić, Borut Peterlin and Nada Starčević Čizmarević

Int. J. Mol. Sci. 2024, 25(13), 7412; https://doi.org/10.3390/ijms25137412 - 5 Jul 2024

Cited by 1 | Viewed by 1977

Abstract

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-β treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders (n = 173) and non-responders (n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence (p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-β therapy in females (p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females (p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-β treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients. Full article

(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)

Review

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51 pages, 2000 KB

Open AccessReview

Leptin as a Potential Modifier of Neuroinflammation: Contrasting Roles in Alzheimer’s Disease and Multiple Sclerosis

by Naghmeh Abbasi Kasbi, Barbara Elena Stopschinski, Alanna Gabrielle Polyak, Agastya Reddy Malladi, Navid Manouchehri, Philipp E. Scherer and Olaf Stuve

Int. J. Mol. Sci. 2026, 27(1), 168; https://doi.org/10.3390/ijms27010168 - 23 Dec 2025

Viewed by 1751

Abstract

The neuroendocrine and immune systems interact bidirectionally through shared ligands and receptors during inflammation, thereby regulating immune responses. Leptin, primarily known for its role in energy metabolism and appetite regulation, also modulates neuroinflammatory pathways. Its receptors are widely expressed on immune cells and contribute to immune mechanisms implicated in the pathogenesis of neuroinflammatory disorders such as multiple sclerosis (MS) and Alzheimer’s disease (AD). This review highlights recent advances in understanding leptin’s role in immune regulation, with a focus on its impact on MS and AD. A comprehensive literature review was conducted until October 2025, using PubMed, Google Scholar, and Scopus to identify studies investigating leptin in neuroinflammatory conditions, particularly MS and AD. Leptin exerts broad immunomodulatory effects by activating T cells, dendritic cells, and microglia, and promoting their proliferation and phagocytosis. Its elevation enhances Th1 and Th17 responses, drives pro-inflammatory macrophage phenotype polarization, and suppresses regulatory T cell and Th2 responses, immune pathways involved in MS. Peripheral leptin levels are increased in MS, especially during disease exacerbations. In contrast, in AD, they are typically reduced, particularly in patients with normal body mass index (BMI), where their decline contributes to amyloid-β and tau pathology. These divergent patterns position leptin as a bidirectional regulator at the intersection of immunity and neurodegeneration. Additionally, its protective or detrimental effects likely depend on whether it acts under physiological conditions or in the context of obesity-induced leptin resistance. Elevated leptin levels in obesity exacerbate inflammation and diminish its neuroprotective effects. In conclusion, leptin is elevated in MS patients but downregulated in AD, reflecting its bidirectional effects. In leptin resistance, peripheral proinflammatory signaling is maintained while central leptin signaling is restricted, thereby potentially promoting autoimmunity in MS and limiting neuroprotection in AD. Further mechanistic and longitudinal studies are needed to clarify the relationship between leptin dysregulation, leptin resistance, neuroinflammatory and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Research and Treatment in Multiple Sclerosis)

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