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Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis
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Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis

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 (31 March 2023) | Viewed by 10688

Special Issue Editors

Prof. Dr. Eleonora Palma

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Guest Editor
Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, 00185 Rome, Italy
Interests: Physiology of neurotransmitter receptors; ALS; epilepsy; nAChRs; GABAARs
Prof. Dr. Maurizio Inghilleri

E-Mail Website
Guest Editor
Rare Neuromuscular Diseases Centre, Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy
Interests: ALS; myasthenia gravis; creatine kinase; neurodegenerative diseases
Prof. Dr. Marco Ceccanti

E-Mail Website
Guest Editor
Rare Neuromuscular Diseases Centre, Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy
Interests: prognosis; ALS; chronic inflammatory demyelinating polyneuropathy; creatine kinase; neurodegenerative diseases
Prof. Dr. Gabriele Ruffolo

E-Mail Website
Guest Editor
Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, 00185 Rome, Italy
Interests: physiology of neurotransmitter receptors; ALS; epilepsy; nAChRs; GABAARs

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS) is a disease associated with both lower and upper motor neuron degeneration and is characterized by severe muscle weakness, eventually culminating in paralysis, and an extremely poor prognosis.

The exact pathogenesis of ALS is still unknown, and many hypotheses are under investigation. Indeed, motor neurons alterations have always been studied, but recent developments have opened new perspectives such as the “dying-back” model, where muscles themselves would be capable of initiating the events leading to the disease, or the “autoimmune hypothesis”, focusing on complement system and inflammation as pathogenic factors. Even genetics is attracting an increased amount of interest, given its possible therapeutic implications.

Despite these efforts, however, there is not yet any solid bridging between basic research progresses, the clinical activity, and the patients themselves. In fact, the treatment options in ALS management are still limited, and in the repertoire of experimental biomarkers and candidate drugs, none have emerged yet. This suggests that this topic still needs deeper investigation.

Here, we aim to gather contributions from basic scientists and clinical researchers to examine the issue of new physiopathological mechanisms, target molecules or biomarkers in ALS from both perspectives, hence promoting a translational and integrated approach to this problem.

Prof. Dr. Eleonora Palma
Prof. Dr. Maurizio Inghilleri
Prof. Dr. Marco Ceccanti
Prof. Dr. Gabriele Ruffolo
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • ALS
  • electrophysiology
  • biomarkers
  • electromyography
  • muscle
  • genetics
  • SOD1

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Published Papers (3 papers)

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Research

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24 pages, 1665 KiB  
Article
The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis
by Elisa Teyssou, Laura Chartier, Delphine Roussel, Nirma D. Perera, Ivan Nemazanyy, Dominique Langui, Mélanie Albert, Thierry Larmonier, Safaa Saker, François Salachas, Pierre-François Pradat, Vincent Meininger, Philippe Ravassard, Francine Côté, Christian S. Lobsiger, Séverine Boillée, Bradley J. Turner, Danielle Seilhean and Stéphanie Millecamps
Int. J. Mol. Sci. 2022, 23(10), 5694; https://doi.org/10.3390/ijms23105694 - 19 May 2022
Cited by 10 | Viewed by 3102
Abstract
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully [...] Read more.
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS. Full article
(This article belongs to the Special Issue Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis)
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19 pages, 3069 KiB  
Article
Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
by Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Giulia Napoli, Mattia Freschi, Francesca Sironi, Paolo Pevarello, Paola Tarroni, Chiara Liberati, Caterina Bendotti and Cinzia Volonté
Int. J. Mol. Sci. 2021, 22(19), 10649; https://doi.org/10.3390/ijms221910649 - 30 Sep 2021
Cited by 14 | Viewed by 3869
Abstract
Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials. Full article
(This article belongs to the Special Issue Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis)
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Review

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14 pages, 985 KiB  
Review
Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us
by Federica Sandrelli and Marco Bisaglia
Int. J. Mol. Sci. 2023, 24(8), 7674; https://doi.org/10.3390/ijms24087674 - 21 Apr 2023
Cited by 3 | Viewed by 2395
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About [...] Read more.
Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About 5–10% of cases have a genetic inheritance, and the study of ALS-associated genes has been fundamental in defining the pathological pathways likely also involved in the sporadic forms of the disease. Mutations affecting the DJ-1 gene appear to explain a subset of familial ALS forms. DJ-1 is involved in multiple molecular mechanisms, acting primarily as a protective agent against oxidative stress. Here, we focus on the involvement of DJ-1 in interconnected cellular functions related to mitochondrial homeostasis, reactive oxygen species (ROS) levels, energy metabolism, and hypoxia response, in both physiological and pathological conditions. We discuss the possibility that impairments in one of these pathways may affect the others, contributing to a pathological background in which additional environmental or genetic factors may act in favor of the onset and/or progression of ALS. These pathways may represent potential therapeutic targets to reduce the likelihood of developing ALS and/or slow disease progression. Full article
(This article belongs to the Special Issue Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis)
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