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Amyotrophic Lateral Sclerosis: Highlights of Its Complexity
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Amyotrophic Lateral Sclerosis: Highlights of Its Complexity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 114771

Special Issue Editors

Dr. Caterina Bendotti

E-Mail Website
Guest Editor
Department of Neuroscience, IRCCS—Institute of Pharmacological Research Mario Negri, 20156 Milano, Italy
Dr. Nicola Ticozzi

E-Mail Website
Guest Editor
Laboratory of Neuroscience, Department of Neurology, Istituto Auxologico Italiano – Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy

Special Issue Information

Dear Colleagues,

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease of the adult, characterized by progressive skeletal muscle paralysis and premature death due to respiratory failure. There is still no effective therapy to prevent the development and progression of this devastating disease, for this reason ALS is currently an area of great interest in research.  In the last 25 years there have been enormous advancements in the identification of genetic risk factors associated with ALS susceptibility, highlighting the genetic and phenotypic heterogeneity of this disease. Thanks to these genetic discoveries and the development of new experimental models of the disease, it has become clear that ALS results from a complex phenomenon involving multifactorial, multicellular and multisystem mechanisms, ultimately leading to the progressive vulnerability and death of the motor neurons.

This Special Issue on ALS aims to review the latest advance in ALS research that include: 1) the new results from the large-scale genome wide association studies (GWAS) and next-generation sequencing; 2) the development of new in vitro and in vivo experimental models tailored to approach the genetic heterogeneity of the disease; 3) the identification of biomarkers that allows to predict the disease progression and to stratify ALS patients for clinical trials; 4) the study of interaction between different cell types in the axis that goes from the central nervous system to the muscle including other components like the immune system; and 5) the examination of strategies that potentially lead to disease-modifying treatments.

Dr. Caterina Bendotti
Dr. Nicola Ticozzi
Guest Editors

Manuscript Submission Information

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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

  • Motor neuron disease
  • Neuromuscular disease
  • Genetics
  • Epigenetics
  • iPSC
  • Glial cells
  • Immune system
  • RNA metabolism
  • Protein aggregation
  • Axonal dysfunction
  • Excitotoxicity
  • Gene therapy
  • Cell therapy

Published Papers (17 papers)

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Research

Jump to: Review

19 pages, 3205 KiB  
Article
A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
by Antonio Vallarola, Massimo Tortarolo, Roberta De Gioia, Luisa Iamele, Hugo de Jonge, Giovanni de Nola, Enrica Bovio, Laura Pasetto, Valentina Bonetto, Mattia Freschi, Caterina Bendotti and Ermanno Gherardi
Int. J. Mol. Sci. 2020, 21(22), 8542; https://doi.org/10.3390/ijms21228542 - 12 Nov 2020
Cited by 6 | Viewed by 2661
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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21 pages, 648 KiB  
Article
Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort
by Stefania Scarlino, Teuta Domi, Laura Pozzi, Alessandro Romano, Giovanni Battista Pipitone, Yuri Matteo Falzone, Lorena Mosca, Silvana Penco, Christian Lunetta, Valeria Sansone, Lucio Tremolizzo, Raffaella Fazio, Federica Agosta, Massimo Filippi, Paola Carrera, Nilo Riva and Angelo Quattrini
Int. J. Mol. Sci. 2020, 21(9), 3346; https://doi.org/10.3390/ijms21093346 - 08 May 2020
Cited by 10 | Viewed by 3630
Abstract
Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of [...] Read more.
Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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16 pages, 2910 KiB  
Article
Inter-Species Differences in Regulation of the Progranulin–Sortilin Axis in TDP-43 Cell Models of Neurodegeneration
by Valentina Gumina, Elisa Onesto, Claudia Colombrita, AnnaMaria Maraschi, Vincenzo Silani and Antonia Ratti
Int. J. Mol. Sci. 2019, 20(23), 5866; https://doi.org/10.3390/ijms20235866 - 22 Nov 2019
Cited by 3 | Viewed by 4207
Abstract
Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. [...] Read more.
Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin–sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin–sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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19 pages, 4678 KiB  
Article
Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression
by Tiziana Bonifacino, Claudia Rebosio, Francesca Provenzano, Carola Torazza, Matilde Balbi, Marco Milanese, Luca Raiteri, Cesare Usai, Ernesto Fedele and Giambattista Bonanno
Int. J. Mol. Sci. 2019, 20(18), 4552; https://doi.org/10.3390/ijms20184552 - 13 Sep 2019
Cited by 14 | Viewed by 3102
Abstract
Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu [...] Read more.
Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1G93A mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1G93A mice. The mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) concentration dependently stimulated the release of [3H]d-Aspartate ([3H]d-Asp), which was comparable in 30- and 60-day-old wild type mice and SOD1G93A mice. At variance, [3H]d-Asp release was significantly augmented in 90-day-old SOD1G93A mice and both mGluR1 and mGluR5 were involved. The 3,5-DHPG-induced [3H]d-Asp release was exocytotic, being of vesicular origin and mediated by intra-terminal Ca2+ release. mGluR1 and mGluR5 expression was increased in Glu spinal cord axon terminals of 90-day-old SOD1G93A mice, but not in the whole axon terminal population. Interestingly, mGluR1 and mGluR5 were significantly augmented in total spinal cord tissue already at 60 days. Thus, function and expression of group I mGluRs are enhanced in the early-symptomatic SOD1G93A mouse spinal cord, possibly participating in excessive Glu transmission and supporting their implication in ALS. Please define all abbreviations the first time they appear in the abstract, the main text, and the first figure or table caption. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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17 pages, 3016 KiB  
Article
CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS
by Mariángeles Kovacs, Emiliano Trias, Valentina Varela, Sofia Ibarburu, Joseph S. Beckman, Ivan C. Moura, Olivier Hermine, Peter H. King, Ying Si, Yuri Kwon and Luis Barbeito
Int. J. Mol. Sci. 2019, 20(16), 3880; https://doi.org/10.3390/ijms20163880 - 09 Aug 2019
Cited by 9 | Viewed by 4691
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS [...] Read more.
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1G93A mutation and autopsied ALS and control human subjects. Characterization of CD34-positive cells was also performed in primary cell cultures of the rat spinal cords. CD34 was expressed in a large number of cells that closely interacted with degenerating lumbar spinal cord motor neurons in symptomatic SOD1G93A rats, but not in controls. Most CD34+ cells co-expressed the myeloid marker CD11b, while only a subpopulation was stained for Iba1 or CD68. Notably, CD34+ cells actively proliferated and formed clusters adjacent to damaged motor neurons bearing misfolded SOD1. CD34+ cells were identified in the proximity of motor neurons in autopsied spinal cord from sporadic ALS subjects but not in controls. Cell culture of symptomatic SOD1G93A rat spinal cords yielded a large number of CD34+ cells exclusively in the non-adherent phase, which generated microglia after successive passaging. A yet unrecognized CD34+ cells, expressing or not the microglial marker Iba1, proliferate and accumulate adjacent to degenerating spinal motor neurons, representing an intriguing cell target for approaching ALS pathogenesis and therapeutics. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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15 pages, 2769 KiB  
Article
Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS
by Savina Apolloni, Francesca Caputi, Annabella Pignataro, Susanna Amadio, Paola Fabbrizio, Martine Ammassari-Teule and Cinzia Volonté
Int. J. Mol. Sci. 2019, 20(15), 3793; https://doi.org/10.3390/ijms20153793 - 03 Aug 2019
Cited by 12 | Viewed by 3734
Abstract
(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having [...] Read more.
(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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24 pages, 5424 KiB  
Article
Experimental Motor Neuron Disease Induced in Mice with Long-Term Repeated Intraperitoneal Injections of Serum from ALS Patients
by Izabella Obál, Bernát Nógrádi, Valéria Meszlényi, Roland Patai, Gerda Ricken, Gabor G. Kovacs, Kornélia Tripolszki, Márta Széll, László Siklós and József I. Engelhardt
Int. J. Mol. Sci. 2019, 20(10), 2573; https://doi.org/10.3390/ijms20102573 - 25 May 2019
Cited by 13 | Viewed by 4118
Abstract
In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons [...] Read more.
In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons was noted, to test whether the ALS IgG in this paradigm has the potential to evoke relentless degeneration of motor neurons, treatment with repeated injections over a longer period was carried out. Mice were systematically injected intraperitoneally with serum taken from ALS patients over a 75-day period. At selected time points, the isometric force of the limbs, number of spinal motor neurons and their intracellular calcium levels were determined. Furthermore, markers of glial activation and the motoneuronal uptake of human IgG were monitored. During this period, gliosis and progressive motoneuronal degeneration developed, which led to gradual loss of spinal motor neurons, more than 40% at day 21, along with decreasing muscle strength in the limbs. The inclusion-like accumulation of IgG appeared in the perikarya with the increase of intracellular calcium in the cell bodies and motor nerve terminals. Our results demonstrate that ALS serum can transfer motor neuron disease to mice. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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16 pages, 2426 KiB  
Article
Impact of Pharmacological Inhibition of Hydrogen Sulphide Production in the SOD1G93A-ALS Mouse Model
by Alida Spalloni, Viviana Greco, Giulia Ciriminna, Victor Corasolla Carregari, Federica Marini, Luisa Pieroni, Nicola B. Mercuri, Andrea Urbani and Patrizia Longone
Int. J. Mol. Sci. 2019, 20(10), 2550; https://doi.org/10.3390/ijms20102550 - 24 May 2019
Cited by 13 | Viewed by 2809
Abstract
A number of factors can trigger amyotrophic lateral sclerosis (ALS), although its precise pathogenesis is still uncertain. In a previous study done by us, poisonous liquoral levels of hydrogen sulphide (H2S) in sporadic ALS patients were reported. In the same study [...] Read more.
A number of factors can trigger amyotrophic lateral sclerosis (ALS), although its precise pathogenesis is still uncertain. In a previous study done by us, poisonous liquoral levels of hydrogen sulphide (H2S) in sporadic ALS patients were reported. In the same study very high concentrations of H2S in the cerebral tissues of the familial ALS (fALS) model of the SOD1G93A mouse, were measured. The objective of this study was to test whether decreasing the levels of H2S in the fALS mouse could be beneficial. Amino-oxyacetic acid (AOA)—a systemic dual inhibitor of cystathionine-β-synthase and cystathionine-γ lyase (two key enzymes in the production of H2S)—was administered to fALS mice. AOA treatment decreased the content of H2S in the cerebral tissues, and the lifespan of female mice increased by approximately ten days, while disease progression in male mice was not affected. The histological evaluation of the spinal cord of the females revealed a significant increase in GFAP positivity and a significant decrease in IBA1 positivity. In conclusion, the results of the study indicate that, in the animal model, the inhibition of H2S production is more effective in females. The findings reinforce the need to adequately consider sex as a relevant factor in ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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24 pages, 2486 KiB  
Article
Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)
by Marina Oaia Iridoy, Irene Zubiri, María Victoria Zelaya, Leyre Martinez, Karina Ausín, Mercedes Lachen-Montes, Enrique Santamaría, Joaquín Fernandez-Irigoyen and Ivonne Jericó
Int. J. Mol. Sci. 2019, 20(1), 4; https://doi.org/10.3390/ijms20010004 - 20 Dec 2018
Cited by 47 | Viewed by 7312
Abstract
(1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping [...] Read more.
(1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping of the spinal cord. (2) Methods: A liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the spinal cord from ALS-TAR DNA-binding protein 43 (TDP-43) subjects, ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) subjects and controls without neurodegenerative disease was performed. (3) Results: 281 differentially expressed proteins were detected among ALS versus controls, while 52 proteins were dysregulated among FTLD-U versus controls. Thirty-three differential proteins were shared between both syndromes. The resulting data was subjected to network-driven proteomics analysis, revealing mitochondrial dysfunction and metabolic impairment, both for ALS and FTLD-U that could be validated through the confirmation of expression levels changes of the Prohibitin (PHB) complex. (4) Conclusions: ALS-TDP-43 and FTLD-U share molecular and functional alterations, although part of the proteostatic impairment is region- and disease-specific. We have confirmed the involvement of specific proteins previously associated with ALS (Galectin 2 (LGALS3), Transthyretin (TTR), Protein S100-A6 (S100A6), and Protein S100-A11 (S100A11)) and have shown the involvement of proteins not previously described in the ALS context (Methanethiol oxidase (SELENBP1), Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN-1), Calcyclin-binding protein (CACYBP) and Rho-associated protein kinase 2 (ROCK2)). Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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Review

Jump to: Research

17 pages, 1308 KiB  
Review
Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis
by Mariarita Galbiati, Valeria Crippa, Paola Rusmini, Riccardo Cristofani, Elio Messi, Margherita Piccolella, Barbara Tedesco, Veronica Ferrari, Elena Casarotto, Marta Chierichetti and Angelo Poletti
Int. J. Mol. Sci. 2020, 21(12), 4291; https://doi.org/10.3390/ijms21124291 - 16 Jun 2020
Cited by 22 | Viewed by 3914
Abstract
Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial [...] Read more.
Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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21 pages, 1331 KiB  
Review
Gene Therapy for ALS—A Perspective
by Marisa Cappella, Chiara Ciotti, Mathilde Cohen-Tannoudji and Maria Grazia Biferi
Int. J. Mol. Sci. 2019, 20(18), 4388; https://doi.org/10.3390/ijms20184388 - 06 Sep 2019
Cited by 63 | Viewed by 15082
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder—particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder—particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND—the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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14 pages, 758 KiB  
Review
Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature
by Delia Gagliardi, Megi Meneri, Domenica Saccomanno, Nereo Bresolin, Giacomo Pietro Comi and Stefania Corti
Int. J. Mol. Sci. 2019, 20(17), 4152; https://doi.org/10.3390/ijms20174152 - 25 Aug 2019
Cited by 44 | Viewed by 4513
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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26 pages, 3521 KiB  
Review
Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons
by Baris Genc, Oge Gozutok and P. Hande Ozdinler
Int. J. Mol. Sci. 2019, 20(16), 3848; https://doi.org/10.3390/ijms20163848 - 07 Aug 2019
Cited by 22 | Viewed by 6555
Abstract
Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in [...] Read more.
Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in which initiation and modulation of voluntary movement is affected. Amyotrophic lateral sclerosis (ALS) is defined by the progressive degeneration of both the upper and lower motor neurons, whereas hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are characterized mainly by the loss of upper motor neurons. In an effort to reveal the cellular and molecular basis of neuronal degeneration, numerous model systems are generated, and mouse models are no exception. However, there are many different levels of complexities that need to be considered when developing mouse models. Here, we focus our attention to the upper motor neurons, which are one of the most challenging neuron populations to study. Since mice and human differ greatly at a species level, but the cells/neurons in mice and human share many common aspects of cell biology, we offer a solution by focusing our attention to the affected neurons to reveal the complexities of diseases at a cellular level and to improve translational efforts. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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32 pages, 1467 KiB  
Review
Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases
by Takashi Hosaka, Takenari Yamashita, Akira Tamaoka and Shin Kwak
Int. J. Mol. Sci. 2019, 20(13), 3148; https://doi.org/10.3390/ijms20133148 - 27 Jun 2019
Cited by 36 | Viewed by 6092
Abstract
Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable [...] Read more.
Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell–cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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16 pages, 2241 KiB  
Review
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques
by Mehdi A. J. van den Bos, Nimeshan Geevasinga, Mana Higashihara, Parvathi Menon and Steve Vucic
Int. J. Mol. Sci. 2019, 20(11), 2818; https://doi.org/10.3390/ijms20112818 - 10 Jun 2019
Cited by 74 | Viewed by 19699
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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17 pages, 282 KiB  
Review
Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?
by Laura Moreno-Martinez, Ana Cristina Calvo, María Jesús Muñoz and Rosario Osta
Int. J. Mol. Sci. 2019, 20(11), 2759; https://doi.org/10.3390/ijms20112759 - 05 Jun 2019
Cited by 29 | Viewed by 3933
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown alterations in levels of numerous cytokines in ALS, supporting the contribution of neuroinflammation to the progressive motor neuron loss. However, none of them is fully sensitive and specific enough to become a universal biomarker for ALS. This review gathers the numerous circulating cytokines that have been found dysregulated in both ALS animal models and patients. Particularly, it highlights the opposing results found in the literature to date, and points out another potential application of inflammatory cytokines as therapeutic targets. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
19 pages, 909 KiB  
Review
Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis
by Natalia Nowicka, Jakub Juranek, Judyta K. Juranek and Joanna Wojtkiewicz
Int. J. Mol. Sci. 2019, 20(11), 2616; https://doi.org/10.3390/ijms20112616 - 28 May 2019
Cited by 65 | Viewed by 16505
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Highlights of Its Complexity)
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