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Research Strategies to Unveil the Genetic and Molecular Basis of...
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Research Strategies to Unveil the Genetic and Molecular Basis of ALS

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Technologies and Resources for Genetics".

Deadline for manuscript submissions: closed (15 July 2024) | Viewed by 23812

Special Issue Editors

Dr. Serena Lattante

E-Mail Website
Guest Editor
Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
Interests: neurodegeneration; amyotrophic lateral sclerosis; human genetics; animal models of genetic diseases; zebrafish
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppe Marangi

E-Mail Website
Guest Editor
Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Interests: medical genomics; clinical genetics; bioinformatics; amyotrophic lateral sclerosis; developmental disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are delighted to announce a call for submissions to a Special Issue of Genes on the topic “Research strategies to unveil the genetic and molecular basis of ALS”.

Amyotrophic lateral sclerosis is a very complex disease caused by genetic and environmental factors, affecting selectively upper and lower motor neurons.  

Genetic causes have been already identified in a subgroup of patients, with pathogenic variants found in a number of genes. Other genes are yet to be identified, although the list of known ALS-associated genes is increasing thanks to the application of novel high-throughput sequencing technologies. The different pathways involved and the pleiotropy of the genes can reflect the clinical heterogeneity observed in patients.

This Special Issue looks to update and advance the current knowledge about genetic causes of ALS, the contribution of predisposing genes, molecular techniques applied to the identification of new genes, and cellular and animal models used to clarify ALS pathogenesis.

Papers providing new insights into ALS genetics and mechanisms and into the relationship between ALS and other neurodegenerative diseases, such as frontotemporal dementia, are welcome.

Please feel free to contact us for any further information about the Special Issue.

Dr. Serena Lattante
Dr. Giuseppe Marangi
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. Genes 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 2600 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

  • amyotrophic lateral sclerosis (ALS)
  • molecular
  • genetics
  • genomics
  • animal models
  • cellular models

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Published Papers (9 papers)

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Research

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16 pages, 1155 KiB  
Article
Phenotypical Characterization of C9ALS Patients from the Emilia Romagna Registry of ALS: A Retrospective Case–Control Study
by Andrea Ghezzi, Giulia Gianferrari, Elisa Baldassarri, Elisabetta Zucchi, Ilaria Martinelli, Veria Vacchiano, Luigi Bonan, Lucia Zinno, Andi Nuredini, Elena Canali, Matteo Gizzi, Emilio Terlizzi, Doriana Medici, Elisabetta Sette, Marco Currò Dossi, Simonetta Morresi, Mario Santangelo, Alberto Patuelli, Marco Longoni, Patrizia De Massis, Salvatore Ferro, Nicola Fini, Cecilia Simonini, Serena Carra, Giovanna Zamboni and Jessica Mandrioliadd Show full author list remove Hide full author list
Genes 2025, 16(3), 309; https://doi.org/10.3390/genes16030309 - 4 Mar 2025
Viewed by 746
Abstract
Background/Objectives: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic [...] Read more.
Background/Objectives: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register. Methods: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex. Results: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients. Conclusions: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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6 pages, 461 KiB  
Article
Exploring the Role of CCNF Variants in Italian ALS Patients
by Giulia Bisogni, Amelia Conte, Umberto Costantino, Serena Lattante, Daniela Bernardo, Gabriele Lucioli, Agata Katia Patanella, Paola Cimbolli, Elda Del Giudice, Federica Vettor, Giuseppe Marangi, Paolo Niccolò Doronzio, Marcella Zollino and Mario Sabatelli
Genes 2024, 15(12), 1566; https://doi.org/10.3390/genes15121566 - 3 Dec 2024
Viewed by 845
Abstract
Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian [...] Read more.
Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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18 pages, 4737 KiB  
Article
Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages
by Elisabetta Carata, Marco Muci, Stefania Mariano, Simona Di Giulio, Annamaria Nigro, Alessandro Romano and Elisa Panzarini
Genes 2024, 15(6), 735; https://doi.org/10.3390/genes15060735 - 3 Jun 2024
Cited by 3 | Viewed by 1616
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs–macrophage [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs–macrophage communication is pivotal. Here, we focus on extracellular vesicle (EVS)-mediated communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. mSOD1 NSC-34 cells release a high number of vesicles, both large-lEVs (300 nm diameter) and small-sEVs (90 nm diameter), containing inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN degeneration. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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12 pages, 752 KiB  
Article
Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review
by Michele Lombardi, Lucia Corrado, Beatrice Piola, Cristoforo Comi, Roberto Cantello, Sandra D’Alfonso, Letizia Mazzini and Fabiola De Marchi
Genes 2023, 14(11), 2039; https://doi.org/10.3390/genes14112039 - 4 Nov 2023
Cited by 5 | Viewed by 2507
Abstract
Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2–5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many [...] Read more.
Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2–5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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16 pages, 3303 KiB  
Article
Generation of an Open-Access Patient-Derived iPSC Biobank for Amyotrophic Lateral Sclerosis Disease Modelling
by Erin C. Hedges, Graham Cocks, Christopher E. Shaw and Agnes L. Nishimura
Genes 2023, 14(5), 1108; https://doi.org/10.3390/genes14051108 - 18 May 2023
Cited by 4 | Viewed by 3288
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, causing patients to lose control over voluntary movement, and leading to gradual paralysis and death. There is no cure for ALS, and the development of viable therapeutics [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, causing patients to lose control over voluntary movement, and leading to gradual paralysis and death. There is no cure for ALS, and the development of viable therapeutics has proved challenging, demonstrated by a lack of positive results from clinical trials. One strategy to address this is to improve the tool kit available for pre-clinical research. Here, we describe the creation of an open-access ALS iPSC biobank generated from patients carrying mutations in the TARDBP, FUS, ANXA11, ARPP21, and C9ORF72 genes, alongside healthy controls. To demonstrate the utilisation of these lines for ALS disease modelling, a subset of FUS-ALS iPSCs were differentiated into functionally active motor neurons. Further characterisation revealed an increase in cytoplasmic FUS protein and reduced neurite outgrowth in FUS-ALS motor neurons compared to the control. This proof-of-principle study demonstrates that these novel patient-derived iPSC lines can recapitulate specific and early disease-related ALS phenotypes. This biobank provides a disease-relevant platform for discovery of ALS-associated cellular phenotypes to aid the development of novel treatment strategies. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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Review

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22 pages, 4103 KiB  
Review
Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS)
by Giovanni Gotte
Genes 2024, 15(6), 738; https://doi.org/10.3390/genes15060738 - 4 Jun 2024
Viewed by 1571
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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14 pages, 962 KiB  
Review
Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges
by Paulo Victor Sgobbi de Souza, Paulo de Lima Serrano, Igor Braga Farias, Roberta Ismael Lacerda Machado, Bruno de Mattos Lombardi Badia, Hélvia Bertoldo de Oliveira, Alana Strucker Barbosa, Camila Alves Pereira, Vanessa de Freitas Moreira, Marco Antônio Troccoli Chieia, Adriel Rêgo Barbosa, Vinícius Lopes Braga, Wladimir Bocca Vieira de Rezende Pinto and Acary Souza Bulle Oliveira
Genes 2024, 15(3), 311; https://doi.org/10.3390/genes15030311 - 28 Feb 2024
Cited by 3 | Viewed by 3728
Abstract
Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. [...] Read more.
Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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20 pages, 1128 KiB  
Review
Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants
by Fabiola De Marchi, Giacomo Tondo, Lucia Corrado, Federico Menegon, Davide Aprile, Matteo Anselmi, Sandra D’Alfonso, Cristoforo Comi and Letizia Mazzini
Genes 2023, 14(8), 1658; https://doi.org/10.3390/genes14081658 - 21 Aug 2023
Cited by 10 | Viewed by 5535
Abstract
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10–15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10–15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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Other

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10 pages, 773 KiB  
Case Report
Young Onset Alzheimer’s Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association
by Giulia Vinceti, Chiara Gallingani, Elisabetta Zucchi, Ilaria Martinelli, Giulia Gianferrari, Cecilia Simonini, Roberta Bedin, Annalisa Chiari, Giovanna Zamboni and Jessica Mandrioli
Genes 2023, 14(4), 930; https://doi.org/10.3390/genes14040930 - 17 Apr 2023
Cited by 2 | Viewed by 2759
Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of [...] Read more.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of patients carrying this expansion varies widely and includes diseases beyond the FTD-ALS spectrum. Although a few cases of patients with C9ORF72 expansion and a clinical or biomarker-supported diagnosis of Alzheimer’s disease (AD) have been described, they have been considered too sparse to establish a definite association between the C9ORF72 expansion and AD pathology. Here, we describe a C9ORF72 family with pleomorphic phenotypical expressions: a 54-year-old woman showing cognitive impairment and behavioral disturbances with both neuroimaging and cerebrospinal fluid (CSF) biomarkers consistent with AD pathology, her 49-year-old brother with typical FTD-ALS, and their 63-year-old mother with the behavioral variant of FTD and CSF biomarkers suggestive of AD pathology. The young onset of disease in all three family members and their different phenotypes and biomarker profiles make the simple co-occurrence of different diseases an extremely unlikely explanation. Our report adds to previous findings and may contribute to further expanding the spectrum of diseases associated with C9ORF72 expansion. Full article
(This article belongs to the Special Issue Research Strategies to Unveil the Genetic and Molecular Basis of ALS)
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