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Biomedicines
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Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology
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Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 33150

Special Issue Editor

Dr. Antonio Canosa

E-Mail Website
Guest Editor
1. ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, 10126 Turin, Italy
2. SC Neurologia 1U, Azienda Ospedaliero-Universitaria Città Della Salute e Della Scienza di Torino, Turin, Italy
3. Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
Interests: neurology; neurodegeneration; Amyotrophic Lateral Sclerosis; brain 18F-FDG-PET

Special Issue Information

Dear Colleagues,

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive degenerative disease of upper and lower motor neurons, usually leading to death within 2–5 years. Approximately 10–20% of patients with ALS show a positive family history. Mendelian gene variations account for about 80% of such cases, while the remaining still have an unknown cause. The same genes found in familial cases can explain up to 14% of apparently sporadic ones. In the last decades the discovery of ALS-related genes has been driven by different approaches, including neuropathology studies, exome and whole genome sequencing, and repeat sequences detection systems. Genome-Wide Association Studies have been employed to identify susceptibility genes and modifiers of phenotype and survival. The knowledge about the genetic architecture of ALS is hugely increasing and its translation to therapeutic approaches seems to be upcoming. Recent advances in ALS genetics, together with studies on cellular and animal models, have pointed out the involvement of several cellular pathways in motor neuron degeneration, including DNA repair, gene expression, RNA metabolism, transport of molecules and vescicles, protein localisation, proteasome activity, lysosomal function, and autophagy. The scope of this special issue is to collect recent advances in ALS genetics and pathophysiology, since the increasing knowledge in this fields might pave the way for more targeted therapeutic approaches.

Dr. Antonio Canosa
Guest Editor

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Keywords

  • Amyotrophic Lateral Sclerosis
  • genetics
  • pathophysiology
  • disease mechanisms
  • motor neuron degeneration
  • translational research

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Published Papers (8 papers)

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Research

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10 pages, 1318 KiB  
Article
The 2-Oxoglutarate Carrier Is S-Nitrosylated in the Spinal Cord of G93A Mutant hSOD1 Mice Resulting in Disruption of Mitochondrial Glutathione Transport
by Daniel A. Linseman, Aimee N. Winter and Heather M. Wilkins
Biomedicines 2023, 11(1), 61; https://doi.org/10.3390/biomedicines11010061 - 27 Dec 2022
Cited by 2 | Viewed by 1815
Abstract
Mitochondrial oxidative stress and dysfunction are strongly implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Glutathione (GSH) is an endogenous antioxidant that exists as distinct cytosolic and mitochondrial pools. The status of the mitochondrial GSH pool is reliant on transport from the [...] Read more.
Mitochondrial oxidative stress and dysfunction are strongly implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Glutathione (GSH) is an endogenous antioxidant that exists as distinct cytosolic and mitochondrial pools. The status of the mitochondrial GSH pool is reliant on transport from the cytosol through the 2-oxoglutarate carrier (OGC), an inner membrane anion carrier. We have previously reported that the outer mitochondrial membrane protein, Bcl-2, directly binds GSH and is a key regulator of OGC-dependent mitochondrial GSH transport. Here, we show that G93A mutant SOD1 (Cu, Zn-superoxide dismutase) reduces the binding of GSH to Bcl-2 and disrupts mitochondrial GSH uptake in vitro. In the G93A mutant hSOD1 mouse model of ALS, mitochondrial GSH is significantly depleted in spinal cord of end-stage mice. Finally, we show that OGC is heavily S-nitrosylated in the spinal cord of end-stage mice and consequently, the GSH uptake capacity of spinal cord mitochondria isolated from these mutant mice is significantly diminished. Collectively, these findings suggest that spinal cord GSH depletion, particularly at the level of the mitochondria, plays a significant role in ALS pathogenesis induced by mutant SOD1. Furthermore, the depletion of mitochondrial GSH in the G93A mutant hSOD1 mouse model may be caused by the S-nitrosylation of OGC and the capacity of mutant SOD1 to disrupt the Bcl-2/GSH interaction, resulting in a disruption of mitochondrial GSH transport. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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20 pages, 1986 KiB  
Article
Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis
by Débora Lanznaster, Clément Bruno, Jérôme Bourgeais, Patrick Emond, Ilyess Zemmoura, Antoine Lefèvre, Pascal Reynier, Sébastien Eymieux, Emmanuelle Blanchard, Patrick Vourc'h, Christian R. Andres, Salah Eddine Bakkouche, Olivier Herault, Luc Favard, Philippe Corcia and Hélène Blasco
Biomedicines 2022, 10(6), 1307; https://doi.org/10.3390/biomedicines10061307 - 2 Jun 2022
Cited by 9 | Viewed by 5780
Abstract
Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients [...] Read more.
Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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20 pages, 46765 KiB  
Article
Cellular Stress Induces Nucleocytoplasmic Transport Deficits Independent of Stress Granules
by Joni Vanneste, Thomas Vercruysse, Steven Boeynaems, Philip Van Damme, Dirk Daelemans and Ludo Van Den Bosch
Biomedicines 2022, 10(5), 1057; https://doi.org/10.3390/biomedicines10051057 - 3 May 2022
Cited by 6 | Viewed by 3320
Abstract
Stress granules are non-membrane bound granules temporarily forming in the cytoplasm in response to stress. Proteins of the nucleocytoplasmic transport machinery were found in these stress granules and it was suggested that stress granules contribute to the nucleocytoplasmic transport defects in several neurodegenerative [...] Read more.
Stress granules are non-membrane bound granules temporarily forming in the cytoplasm in response to stress. Proteins of the nucleocytoplasmic transport machinery were found in these stress granules and it was suggested that stress granules contribute to the nucleocytoplasmic transport defects in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The aim of this study was to investigate whether there is a causal link between stress granule formation and nucleocytoplasmic transport deficits. Therefore, we uncoupled stress granule formation from cellular stress while studying nuclear import. This was carried out by preventing cells from assembling stress granules despite being subjected to cellular stress either by knocking down both G3BP1 and G3BP2 or by pharmacologically inhibiting stress granule formation. Conversely, we induced stress granules by overexpressing G3BP1 in the absence of cellular stress. In both conditions, nuclear import was not affected demonstrating that stress granule formation is not a direct cause of stress-induced nucleocytoplasmic transport deficits. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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19 pages, 3792 KiB  
Article
LncRNAs Associated with Neuronal Development and Oncogenesis Are Deregulated in SOD1-G93A Murine Model of Amyotrophic Lateral Sclerosis
by Federica Rey, Stefania Marcuzzo, Silvia Bonanno, Matteo Bordoni, Toniella Giallongo, Claudia Malacarne, Cristina Cereda, Gian Vincenzo Zuccotti and Stephana Carelli
Biomedicines 2021, 9(7), 809; https://doi.org/10.3390/biomedicines9070809 - 13 Jul 2021
Cited by 9 | Viewed by 2456
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease caused in 10% of cases by inherited mutations considered “familial”. An ever-increasing amount of evidence is showing a fundamental role for RNA metabolism in ALS pathogenesis, and long non-coding RNAs (lncRNAs) appear to play [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease caused in 10% of cases by inherited mutations considered “familial”. An ever-increasing amount of evidence is showing a fundamental role for RNA metabolism in ALS pathogenesis, and long non-coding RNAs (lncRNAs) appear to play a role in ALS development. Here, we aim to investigate the expression of a panel of lncRNAs (linc-Enc1, linc–Brn1a, linc–Brn1b, linc-p21, Hottip, Tug1, Eldrr, and Fendrr) which could be implicated in early phases of ALS. Via Real-Time PCR, we assessed their expression in a murine familial model of ALS (SOD1-G93A mouse) in brain and spinal cord areas of SOD1-G93A mice in comparison with that of B6.SJL control mice, in asymptomatic (week 8) and late-stage disease (week 18). We highlighted a specific area and pathogenetic-stage deregulation in each lncRNA, with linc-p21 being deregulated in all analyzed tissues. Moreover, we analyzed the expression of their human homologues in SH-SY5Y-SOD1-WT and SH-SY5Y-SOD1-G93A, observing a profound alteration in their expression. Interestingly, the lncRNAs expression in our ALS models often resulted opposite to that observed for the lncRNAs in cancer. These evidences suggest that lncRNAs could be novel disease-modifying agents, biomarkers, or pathways affected by ALS neurodegeneration. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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Review

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15 pages, 1113 KiB  
Review
Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?
by Belén Proaño, Julia Casani-Cubel, María Benlloch, Ana Rodriguez-Mateos, Esther Navarro-Illana, Jose María Lajara-Romance and Jose Enrique de la Rubia Ortí
Biomedicines 2022, 10(9), 2084; https://doi.org/10.3390/biomedicines10092084 - 25 Aug 2022
Cited by 3 | Viewed by 5914
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17β-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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22 pages, 1261 KiB  
Review
How Are Adenosine and Adenosine A2A Receptors Involved in the Pathophysiology of Amyotrophic Lateral Sclerosis?
by Akihisa Mori, Brittany Cross, Shinichi Uchida, Jill Kerrick Walker and Robert Ristuccia
Biomedicines 2021, 9(8), 1027; https://doi.org/10.3390/biomedicines9081027 - 17 Aug 2021
Cited by 6 | Viewed by 3503
Abstract
Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson’s disease, and there is now growing interest in [...] Read more.
Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson’s disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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13 pages, 875 KiB  
Review
NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis
by Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, Ryan W. Dellinger and José M. Estrela
Biomedicines 2021, 9(8), 1000; https://doi.org/10.3390/biomedicines9081000 - 12 Aug 2021
Cited by 8 | Viewed by 4831
Abstract
Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS [...] Read more.
Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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12 pages, 440 KiB  
Review
Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis
by TG Sahana and Ke Zhang
Biomedicines 2021, 9(8), 969; https://doi.org/10.3390/biomedicines9080969 - 6 Aug 2021
Cited by 32 | Viewed by 4318
Abstract
Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of [...] Read more.
Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates. Full article
(This article belongs to the Special Issue Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology)
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