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15 pages, 2467 KiB

Open AccessArticle

Characterization of SOD1-DT, a Divergent Long Non-Coding RNA in the Locus of the SOD1 Human Gene

by Marika Guerra, Lucia Meola, Serena Lattante, Amelia Conte, Mario Sabatelli, Claudio Sette and Camilla Bernardini

Cells 2023, 12(16), 2058; https://doi.org/10.3390/cells12162058 - 13 Aug 2023

Cited by 2 | Viewed by 1590

Abstract

Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the [...] Read more.

Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the mutated genes and its onset has not yet been fully elucidated. Among the genes associated with ALS, superoxide dismutase 1 (SOD1) was the first to be identified, but its role in the etiopathogenesis of the disease is still unclear. In recent years, research has been focused on the non-coding part of the genome to fully understand the mechanisms underlying gene regulation. Non-coding RNAs are conserved molecules and are not usually translated in protein. A total of 98% of the human genome is composed of non-protein coding sequences with roles in the transcriptional and post-transcriptional regulation of gene expression. In this study, we characterized a divergent nuclear lncRNA (SOD1-DT) transcribed in the antisense direction from the 5′ region of the SOD1 coding gene in both the SH-SY5Y cell line and fibroblasts derived from ALS patients. Interestingly, this lncRNA seems to regulate gene expression, since its inhibition leads to the upregulation of surrounding genes including SOD1. SOD1-DT represents a very complex molecule, displaying allelic and transcriptional variability concerning transposable elements (TEs) included in its sequence, widening the scenario of gene expression regulation in ALS disease. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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19 pages, 5298 KiB

Open AccessArticle

C9orf72 Toxic Species Affect ArfGAP-1 Function

by Simona Rossi, Michela Di Salvio, Marilisa Balì, Assia De Simone, Savina Apolloni, Nadia D’Ambrosi, Ivan Arisi, Francesca Cipressa, Mauro Cozzolino and Gianluca Cestra

Cells 2023, 12(15), 2007; https://doi.org/10.3390/cells12152007 - 5 Aug 2023

Cited by 1 | Viewed by 1631

Abstract

Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates [...] Read more.

Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs. We previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in the cell nuclei. To further characterize the process, we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS RNA repeats. Interestingly, pathway analysis showed that the mRNAs involved in membrane trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicated that C9orf72 toxic species affect the membrane trafficking route regulated by ADP-Ribosylation Factor 1 GTPase Activating Protein (ArfGAP-1), which exerts its GTPase-activating function on the small GTPase ADP-ribosylation factor 1 to dissociate coat proteins from Golgi-derived vesicles. We demonstrate that the function of ArfGAP-1 is specifically affected by expanded C9orf72 RNA repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), indicating the retrograde Golgi-to-ER vesicle-mediated transport as a target of C9orf72 toxicity. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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28 pages, 5518 KiB

Open AccessArticle

Genetic Downregulation of the Metabotropic Glutamate Receptor Type 5 Dampens the Reactive and Neurotoxic Phenotype of Adult ALS Astrocytes

by Carola Torazza, Francesca Provenzano, Elena Gallia, Maria Cerminara, Matilde Balbi, Tiziana Bonifacino, Sara Tessitore, Silvia Ravera, Cesare Usai, Ilaria Musante, Aldamaria Puliti, Ludo Van Den Bosch, Paymaan Jafar-nejad, Frank Rigo, Marco Milanese and Giambattista Bonanno

Cells 2023, 12(15), 1952; https://doi.org/10.3390/cells12151952 - 27 Jul 2023

Cited by 4 | Viewed by 2176

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs). Astrocytes display a toxic phenotype in ALS, which results in MN damage. Glutamate (Glu)-mediated excitotoxicity and group I metabotropic glutamate receptors (mGluRs) play a pathological role [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs). Astrocytes display a toxic phenotype in ALS, which results in MN damage. Glutamate (Glu)-mediated excitotoxicity and group I metabotropic glutamate receptors (mGluRs) play a pathological role in the disease progression. We previously demonstrated that in vivo genetic ablation or pharmacological modulation of mGluR5 reduced astrocyte activation and MN death, prolonged survival and ameliorated the clinical progression in the SOD1^G93A mouse model of ALS. This study aimed to investigate in vitro the effects of mGluR5 downregulation on the reactive spinal cord astrocytes cultured from adult late symptomatic SOD1^G93A mice. We observed that mGluR5 downregulation in SOD1^G93A astrocytes diminished the cytosolic Ca²⁺ overload under resting conditions and after mGluR5 simulation and reduced the expression of the reactive glial markers GFAP, S100β and vimentin. In vitro exposure to an anti-mGluR5 antisense oligonucleotide or to the negative allosteric modulator CTEP also ameliorated the altered reactive astrocyte phenotype. Downregulating mGluR5 in SOD1^G93A mice reduced the synthesis and release of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and ameliorated the cellular bioenergetic profile by improving the diminished oxygen consumption and ATP synthesis and by lowering the excessive lactate dehydrogenase activity. Most relevantly, mGluR5 downregulation hampered the neurotoxicity of SOD1^G93A astrocytes co-cultured with spinal cord MNs. We conclude that selective reduction in mGluR5 expression in SOD1^G93A astrocytes positively modulates the astrocyte reactive phenotype and neurotoxicity towards MNs, further supporting mGluR5 as a promising therapeutic target in ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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15 pages, 7940 KiB

Open AccessArticle

CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A

by Valentina La Cognata, Agata Grazia D’Amico, Grazia Maugeri, Giovanna Morello, Maria Guarnaccia, Benedetta Magrì, Eleonora Aronica, Velia D’Agata and Sebastiano Cavallaro

Cells 2023, 12(14), 1813; https://doi.org/10.3390/cells12141813 - 9 Jul 2023

Cited by 4 | Viewed by 1682

Abstract

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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24 pages, 31703 KiB

Open AccessArticle

Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis

by Saiswaroop Rajaratnam, Akhil P. Soman, Kanikaram Sai Phalguna, Sai Sanwid Pradhan, Meghana Manjunath, Raksha Kanthavara Rao, Rajesh Babu Dandamudi, Sai Krishna Srimadh Bhagavatham, Sujith Kumar Pulukool, Sriram Rathnakumar, Sai Kocherlakota, Ashish Pargaonkar, Ravindra P. Veeranna, Natarajan Arumugam, Abdulrahman I. Almansour, Bibha Choudhary and Venketesh Sivaramakrishnan

Cells 2023, 12(9), 1228; https://doi.org/10.3390/cells12091228 - 24 Apr 2023

Cited by 7 | Viewed by 3069

Abstract

Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients and model systems like mice and yeast have helped in understanding the association of various signaling and metabolic pathways with the disease. The yeast model system has played a pivotal role in elucidating the gene amyloid interactions. We carried out an integrated transcriptomic and metabolomic analysis of the TDP-43 expressing yeast model to elucidate deregulated pathways associated with the disease. The analysis shows the deregulation of the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism. Transcriptomic analysis of GEO datasets of TDP-43 expressing motor neurons from mice models of ALS and ALS patients shows considerable overlap with experimental results. Furthermore, a yeast model was used to validate the obtained results using metabolite addition and gene knock-out experiments. Taken together, our result shows a potential role for the TCA cycle, cellular redox pathway, NAD metabolism, and fatty acid metabolism in disease. Supplementation of reduced glutathione, nicotinate, and the keto diet might help to manage the disease. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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15 pages, 3115 KiB

Open AccessArticle

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

by Michael S. McGrath, Rongzhen Zhang, Paige M. Bracci, Ari Azhir and Bruce D. Forrest

Cells 2023, 12(7), 1031; https://doi.org/10.3390/cells12071031 - 28 Mar 2023

Cited by 6 | Viewed by 3287

Abstract

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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20 pages, 5703 KiB

Open AccessArticle

Intramuscular IL-10 Administration Enhances the Activity of Myogenic Precursor Cells and Improves Motor Function in ALS Mouse Model

by Paola Fabbrizio, Cassandra Margotta, Jessica D’Agostino, Giuseppe Suanno, Lorenzo Quetti, Caterina Bendotti and Giovanni Nardo

Cells 2023, 12(7), 1016; https://doi.org/10.3390/cells12071016 - 26 Mar 2023

Cited by 5 | Viewed by 3036

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, with a poor prognosis, a highly unmet therapeutic need, and a burden on health care costs. Hitherto, strategies aimed at protecting motor neurons have missed or modestly delayed ALS due to [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, with a poor prognosis, a highly unmet therapeutic need, and a burden on health care costs. Hitherto, strategies aimed at protecting motor neurons have missed or modestly delayed ALS due to a failure in countering the irreversible muscular atrophy. We recently provided direct evidence underlying the pivotal role of macrophages in preserving skeletal muscle mass. Based on these results, we explored whether the modulation of macrophage muscle response and the enhancement of satellite cell differentiation could effectively promote the generation of new myofibers and counteract muscle dysfunction in ALS mice. For this purpose, disease progression and the survival of SOD1G93A mice were evaluated following IL-10 injections in the hindlimb skeletal muscles. Thereafter, we used ex vivo methodologies and in vitro approaches on primary cells to assess the effect of the treatment on the main pathological signatures. We found that IL-10 improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of macrophages. This resulted in delayed muscle atrophy and motor neuron loss. Our findings provide the basis for a suitable adjunct multisystem therapeutic approach that pinpoints a primary role of muscle pathology in ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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16 pages, 2019 KiB

Open AccessArticle

Development of a Nanoparticle-Based Approach for the Blood–Brain Barrier Passage in a Murine Model of Amyotrophic Lateral Sclerosis

by Martina Bruna Violatto, Laura Pasetto, Elisabetta Casarin, Camilla Tondello, Elisa Schiavon, Laura Talamini, Gloria Marchini, Alfredo Cagnotto, Annalisa Morelli, Alessia Lanno, Alice Passoni, Paolo Bigini, Margherita Morpurgo and Valentina Bonetto

Cells 2022, 11(24), 4003; https://doi.org/10.3390/cells11244003 - 10 Dec 2022

Cited by 3 | Viewed by 2377

Abstract

The development of nanoparticles (NPs) to enable the passage of drugs across blood–brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, [...] Read more.

The development of nanoparticles (NPs) to enable the passage of drugs across blood–brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, we investigated whether the functionalization of avidin-nucleic-acid-nanoassembly (ANANAS) with apolipoprotein E (ApoE) would allow BBB passage in the SOD1^G93A mouse model of amyotrophic lateral sclerosis. Our results demonstrated that ANANAS was able to transiently cross BBB to reach the central nervous system (CNS), and ApoE did not enhance this property. Next, we investigated if ANANAS could improve CNS drug delivery. To this aim, the steroid dexamethasone was covalently linked to ANANAS through an acid-reversible hydrazone bond. Our data showed that the steroid levels in CNS tissues of SOD1^G93A mice treated with nanoformulation were below the detection limit. This result demonstrates that the passage of BBB is not sufficient to guarantee the release of the cargo in CNS and that a different strategy for drug tethering should be devised. The present study furthermore highlights that NPs can be useful in improving the passage through biological barriers but may limit the interaction of the therapeutic compound with the specific target. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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29 pages, 5103 KiB

Open AccessArticle

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

by Francesca Provenzano, Sophie Nyberg, Debora Giunti, Carola Torazza, Benedetta Parodi, Tiziana Bonifacino, Cesare Usai, Nicole Kerlero de Rosbo, Marco Milanese, Antonio Uccelli, Pamela J. Shaw, Laura Ferraiuolo and Giambattista Bonanno

Cells 2022, 11(23), 3923; https://doi.org/10.3390/cells11233923 - 4 Dec 2022

Cited by 20 | Viewed by 3958

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1^G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1^G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes’ neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1^G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1^G93A astrocytes with single miRNA mimics reduced astrocytes’ activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes’ reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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15 pages, 2733 KiB

Open AccessArticle

Evaluation of the Hematological and Serum Biochemistry Parameters in the Pre-Symptomatic and Symptomatic Stages of ALS Disease to Support Early Diagnosis and Prognosis

by Duygu Aydemir, Selcuk Surucu, Ayse Nazli Basak and Nuriye Nuray Ulusu

Cells 2022, 11(22), 3569; https://doi.org/10.3390/cells11223569 - 11 Nov 2022

Cited by 3 | Viewed by 1845

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Since there are no pathognomonic tests for ALS prognoses; clinical diagnoses of the disease take time and are usually difficult. Prognostic biomarkers are urgently needed for rapid and effective ALS prognoses. Male [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Since there are no pathognomonic tests for ALS prognoses; clinical diagnoses of the disease take time and are usually difficult. Prognostic biomarkers are urgently needed for rapid and effective ALS prognoses. Male albino rats were divided into ten groups based on age: 0 (40–45 days old), A (70–75 days old), B (90–95 days old), C (110–115 days old), and D (130–135 days old). Each group was divided into two subgroups according to its mutation status: wild type (SOD1^WT) or mutated (SOD1^G93A). Serum biochemistry and hematological parameters were measured in 90 rats to evaluate possible biomarkers for faster ALS diagnoses and prognoses. Weight loss, cholesterol, creatinine, glucose, total bilirubin (TBIL), blood urine nitrogen (BUN), c-peptide, glucagon, PYY, white blood cell (WBC), lymphocyte (LYM), monocyte (MID), granulocyte (GRAN), red cell distribution width with standard deviation (RDW-SD), red cell distribution width with the coefficient of variation (RDW-CV), platelet (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and procalcitonin (PCT) levels were changed in the SOD1^G93A rats compared to the SOD1^WT rats independently from aging. For the first time in the literature, we showed promising hematological and serum biochemistry parameters in the pre-symptomatic and symptomatic stages of ALS by eliminating the effects of aging. Our results can be used for early diagnoses and prognoses of ALS, improving the quality of life and survival time of ALS patients. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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Review

Jump to: Research

19 pages, 2191 KiB

Open AccessReview

Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets

by Takashi Hosaka, Hiroshi Tsuji and Shin Kwak

Cells 2023, 12(10), 1443; https://doi.org/10.3390/cells12101443 - 22 May 2023

Cited by 5 | Viewed by 2908

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, [...] Read more.

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca²⁺ influx through Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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30 pages, 10462 KiB

Open AccessReview

Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis

by Sumit Kinger, Ankur Rakesh Dubey, Prashant Kumar, Yuvraj Anandrao Jagtap, Akash Choudhary, Amit Kumar, Vijay Kumar Prajapati, Rohan Dhiman and Amit Mishra

Cells 2023, 12(9), 1302; https://doi.org/10.3390/cells12091302 - 2 May 2023

Cited by 8 | Viewed by 4416

Abstract

Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones’ involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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15 pages, 6959 KiB

Open AccessReview

Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis

by Gerald W. Dorn II

Cells 2023, 12(8), 1188; https://doi.org/10.3390/cells12081188 - 19 Apr 2023

Cited by 1 | Viewed by 2022

Abstract

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic [...] Read more.

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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19 pages, 365 KiB

Open AccessReview

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

by Daniel Sanchez-Tejerina, Arnau Llaurado, Javier Sotoca, Veronica Lopez-Diego, Jose M. Vidal Taboada, Maria Salvado and Raul Juntas-Morales

Cells 2023, 12(8), 1180; https://doi.org/10.3390/cells12081180 - 18 Apr 2023

Cited by 5 | Viewed by 3439

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical [...] Read more.

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the “fit-for-purpose” concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

23 pages, 1598 KiB

Open AccessReview

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

by Stefanie Schreiber, Jose Bernal, Philipp Arndt, Frank Schreiber, Patrick Müller, Lorena Morton, Rüdiger Christian Braun-Dullaeus, Maria Del Carmen Valdés-Hernández, Roberto Duarte, Joanna Marguerite Wardlaw, Sven Günther Meuth, Grazia Mietzner, Stefan Vielhaber, Ildiko Rita Dunay, Alexander Dityatev, Solveig Jandke and Hendrik Mattern

Cells 2023, 12(6), 957; https://doi.org/10.3390/cells12060957 - 21 Mar 2023

Cited by 11 | Viewed by 3637

Abstract

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood [...] Read more.

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)

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Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies

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