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Biomedicines
Special Issues
Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum
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Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 8018

Special Issue Editors

Dr. Juan Francisco Vázquez-Costa

E-Mail Website
Guest Editor
Hospital Universitari i Politècnic La Fe, Valencia, Spain
Interests: amyotrophic lateral sclerosis; neuroinflammation; genetics; biomarkers; neuroimaging
Dr. Laura Moreno-Martínez

E-Mail Website
Guest Editor
LAGENBIO, University of Zaragoza, Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Aragon Institute for Health Research (IIS Aragon), Calle Miguel Servet 13, 50013 Zaragoza, Spain
Interests: amyotrophic lateral sclerosis; neuroinflammation; SOD1G93A; biomarkers

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder characterized by progressive loss of motor neurons and a fatal disease course in most patients. Frontotemporal dementia (FTD) is the fourth most common neurodegenerative disorder and overlaps with ALS at a genetic, neuropathological, and clinical level. Both diseases share common molecular mechanisms and are now considered to be part of the same disease spectrum (“ALS-FTD spectrum”). Most ALS and FTD patients are sporadic of unknown cause, whereas mendelian mutation can be found in 10–15% of them. The exact molecular paths leading to neurodegeneration in these diseases is not well known, albeit several mechanisms have been shown to be involved, including alterations in RNA metabolism, processing of aberrant proteins and aggregation, mitochondrial alterations, glial activation and neuroinflammation, axonal transport damage, and excitotoxicity. As a consequence, no effective treatments have been found to date.

This Special Issue of Biomedicines aims to cover the mechanisms of neurodegeneration occurring in ALS and FTD from different perspectives, including but not limited to:

  • Genetics and epigenetics;
  • Neuroinflammation;
  • Protein aggregation;
  • Mitochondrial damage;
  • Excitotoxicity;
  • Novel mechanisms;
  • Neurodegeneration biomarkers;
  • Disease spread mechanisms;
  • Therapeutical approaches to arrest neurodegeneration.

Molecular, cellular, and translational research (including research carried out on animal models and/or patients) is welcomed for this Special Issue.

Dr. Juan Francisco Vázquez-Costa
Dr. Laura Moreno-Martínez
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. Biomedicines 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
  • frontotemporal dementia
  • neurodegeneration
  • genetics
  • epigenetics
  • neuroinflammation
  • pathophysiology
  • RNA metabolism
  • protein aggregation
  • biomarkers
  • therapeutical approaches

Published Papers (4 papers)

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Research

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13 pages, 1247 KiB  
Article
Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population
by Daniel Borrego-Hernández, Juan Francisco Vázquez-Costa, Raúl Domínguez-Rubio, Laura Expósito-Blázquez, Elena Aller, Ariadna Padró-Miquel, Pilar García-Casanova, María J. Colomina, Cristina Martín-Arriscado, Rosario Osta, Pilar Cordero-Vázquez, Jesús Esteban-Pérez, Mónica Povedano-Panadés and Alberto García-Redondo
Biomedicines 2024, 12(2), 356; https://doi.org/10.3390/biomedicines12020356 - 2 Feb 2024
Cited by 1 | Viewed by 1185
Abstract
Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different [...] Read more.
Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471–4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558–3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093–4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375–4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype. Full article
(This article belongs to the Special Issue Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum)
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18 pages, 3233 KiB  
Article
GJA1/CX43 High Expression Levels in the Cervical Spinal Cord of ALS Patients Correlate to Microglia-Mediated Neuroinflammatory Profile
by Nunzio Vicario, Paola Castrogiovanni, Rosa Imbesi, Sebastiano Giallongo, Giuliana Mannino, Debora Lo Furno, Rosario Giuffrida, Agata Zappalà, Giovanni Li Volti, Daniele Tibullo, Michelino Di Rosa and Rosalba Parenti
Biomedicines 2022, 10(9), 2246; https://doi.org/10.3390/biomedicines10092246 - 10 Sep 2022
Cited by 5 | Viewed by 2137
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motoneurons (MNs) with a fatal outcome. The typical degeneration of cortico-spinal, spinal, and bulbar MNs, observed in post-mortem biopsies, is associated with the activation of neuroimmune cells. GJA1, a member of the connexins [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motoneurons (MNs) with a fatal outcome. The typical degeneration of cortico-spinal, spinal, and bulbar MNs, observed in post-mortem biopsies, is associated with the activation of neuroimmune cells. GJA1, a member of the connexins (Cxs) gene family, encodes for connexin 43 (Cx43), a core gap junctions (GJs)- and hemichannels (HCs)-forming protein, involved in cell death, proliferation, and differentiation. Recently, Cx43 expression was found to play a role in ALS pathogenesis. Here, we used microarray and RNA-seq datasets from the NCBI of the spinal cord of control (NDC) and ALS patients, which were stratified according to the GJA1 gene expression. Genes that positively or negatively correlated to GJA1 expression were used to perform a genomic deconvolution analysis (GDA) using neuroimmune signatures. Expression analysis revealed a significantly higher GJA1 expression in the MNs of ALS patients as compared to NDC. Gene deconvolution analysis revealed that positively correlated genes were associated with microglia activation, whereas negatively correlated genes were associated with neuronal activation profiles. Moreover, gene ontology analysis, performed on genes characterizing either microglia or neuronal signature, indicated immune activation or neurogenesis as main biological processes. Finally, using a synthetic analysis of drugs able to revert the GJA1 transcriptomic signatures, we found a specific drug profile for ALS patients with high GJA1 expression levels, composed of amlodipine, sertraline, and prednisolone. In conclusion, our exploratory study suggests GJA1 as a new neuro-immunological gene correlated to microglial cellular profile in the spinal cord of ALS patients. Further studies are warranted to confirm these results and to evaluate the therapeutic potential of drugs able to revert typical GJA1/CX43 signature in ALS patients Full article
(This article belongs to the Special Issue Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum)
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Review

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20 pages, 1325 KiB  
Review
Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy
by Soju Seki, Yoshihiro Kitaoka, Sou Kawata, Akira Nishiura, Toshihiro Uchihashi, Shin-ichiro Hiraoka, Yusuke Yokota, Emiko Tanaka Isomura, Mikihiko Kogo and Susumu Tanaka
Biomedicines 2023, 11(11), 2967; https://doi.org/10.3390/biomedicines11112967 - 3 Nov 2023
Cited by 1 | Viewed by 2042
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons. Full article
(This article belongs to the Special Issue Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum)
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Other

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11 pages, 1346 KiB  
Brief Report
Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis
by Carlota Jauregui, Idoia Blanco-Luquin, Mónica Macías, Miren Roldan, Cristina Caballero, Inma Pagola, Maite Mendioroz and Ivonne Jericó
Biomedicines 2023, 11(11), 2994; https://doi.org/10.3390/biomedicines11112994 - 8 Nov 2023
Viewed by 1840
Abstract
Background: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying [...] Read more.
Background: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord. Methods: We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank. Results: The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL. Conclusions: This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS. Full article
(This article belongs to the Special Issue Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum)
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