scholarly journals Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 565
Author(s):  
Stefano Raffaele ◽  
Marta Boccazzi ◽  
Marta Fumagalli
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Therapeutic Interventions ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Precursor ◽  
Spontaneous Regeneration ◽  
The Impact ◽  
Lateral Sclerosis ◽  
Myelin Damage

Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.

scholarly journals Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1210
Author(s):  
Júlia Costa ◽  
Marta Gromicho ◽  
Ana Pronto-Laborinho ◽  
Conceição Almeida ◽  
Ricardo A. Gomes ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Disease Diagnosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Progression Rate ◽  
Therapeutic Trials ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

scholarly journals Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Iris-Stefania Pasniceanu ◽  
Manpreet Singh Atwal ◽  
Cleide Dos Santos Souza ◽  
Laura Ferraiuolo ◽  
Matthew R. Livesey
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Repeat Expansion ◽  
Neuronal Function ◽  
Repeat Expansion Mutation ◽  
Expansion Mutation ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

Early gastrostomy associated with speech therapy in patients with amyotrophic lateral sclerosis

2018 ◽  
Vol 19 (3) ◽  
pp. 414
Author(s):  
Viviane Marques ◽  
Marco Orsini ◽  
Rossano Fiorelli ◽  
Victor Hugo Bastos ◽  
Silmar Teixeira ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Deglutition Disorders ◽  
Motor Neurons ◽  
Speech Therapy ◽  
Life Time ◽  
Breathing Disorders ◽  
Clinical Impairment ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease that occurs with the deterioration of motor neurons. The beginning of clinical impairment may be bulbar with the average life time, after the first symptoms, between 2 to 5 years, presenting serious swallowing, speech and breathing disorders. Deglutition disorders can lead to malnutrition, dehydration, aspiration, displeasure, and more serious complications such as aspiration pneumonia and death. With the evolution of the disease, the patient needs procedures that generate doubts in the professionals and family, as the correct moment of indication of the use of alternative long-term feeding routes called gastrostomies (GTT). The objective of this article is to analyze the impact of dysphagias and the most favorable moment for the placement of gastrostomies. Early GTT placement may help prevent the patient from clinically debilitating more quickly, respond better to multidisciplinary team therapeutics, and feel more comfortable.Key-words: dysphagia, enteral nutrition, gastrostomy, deglutition disorders, motor neuron disease, amyotrophic lateral sclerosis.

scholarly journals Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review

2021 ◽  
Vol 11 (5) ◽  
pp. 549
Author(s):  
Jonu Pradhan ◽  
Mark C. Bellingham
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Pathological Process ◽  
Synaptic Activity ◽  
Cellular Mechanisms ◽  
Animal Disease Models ◽  
Neurophysiological Mechanisms ◽  
Novel Therapeutic Strategies ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease.

scholarly journals Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

2020 ◽  
Vol 9 ◽  
Author(s):  
Lauren M Gittings ◽  
Rita Sattler
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Clinical Stage ◽  
Treatment Options ◽  
Therapeutic Interventions ◽  
Current Status ◽  
Stage Of Development ◽  
Recent Advances ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.

scholarly journals Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

2015 ◽  
Vol 113 (3) ◽  
pp. 614-619 ◽  
Author(s):  
Elizabeth A. Proctor ◽  
Lanette Fee ◽  
Yazhong Tao ◽  
Rachel L. Redler ◽  
James M. Fay ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Molecular Etiology ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.

scholarly journals MicroRNAs as Biomarkers in Amyotrophic Lateral Sclerosis

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 219 ◽  
Author(s):  
Claudia Ricci ◽  
Carlotta Marzocchi ◽  
Stefania Battistini
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
High Specificity ◽  
Practical Applications ◽  
Advantages And Disadvantages ◽  
Specificity And Sensitivity ◽  
Sporadic Als ◽  
History Of ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal disorder characterized by the progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord. Sporadic ALS form accounts for the majority of patients, but in 1–13.5% of cases the disease is inherited. The diagnosis of ALS is mainly based on clinical assessment and electrophysiological examinations with a history of symptom progression and is then made with a significant delay from symptom onset. Thus, the identification of biomarkers specific for ALS could be of a fundamental importance in the clinical practice. An ideal biomarker should display high specificity and sensitivity for discriminating ALS from control subjects and from ALS-mimics and other neurological diseases, and should then monitor disease progression within individual patients. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases, since they are remarkably stable in human body fluids and can reflect physiological and pathological processes relevant for ALS. Here, we review the state of the art of miRNA biomarker identification for ALS in cerebrospinal fluid (CSF), blood and muscle tissue; we discuss advantages and disadvantages of different approaches, and underline the limits but also the great potential of this research for future practical applications.

scholarly journals RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases

2021 ◽  
Vol 22 (20) ◽  
pp. 10958
Author(s):  
Takashi Hosaka ◽  
Hiroshi Tsuji ◽  
Shin Kwak
Keyword(s):  
Gene Therapy ◽  
Amyotrophic Lateral Sclerosis ◽  
Rna Editing ◽  
Motor Neurons ◽  
Ampa Receptors ◽  
Neurological Diseases ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Therapeutic Opportunity ◽  
Central Nervous Systems ◽  
Lateral Sclerosis

The conversion of adenosine to inosine in RNA editing (A-to-I RNA editing) is recognized as a critical post-transcriptional modification of RNA by adenosine deaminases acting on RNAs (ADARs). A-to-I RNA editing occurs predominantly in mammalian and human central nervous systems and can alter the function of translated proteins, including neurotransmitter receptors and ion channels; therefore, the role of dysregulated RNA editing in the pathogenesis of neurological diseases has been speculated. Specifically, the failure of A-to-I RNA editing at the glutamine/arginine (Q/R) site of the GluA2 subunit causes excessive permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to Ca2+, inducing fatal status epilepticus and the neurodegeneration of motor neurons in mice. Therefore, an RNA editing deficiency at the Q/R site in GluA2 due to the downregulation of ADAR2 in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients suggests that Ca2+-permeable AMPA receptors and the dysregulation of RNA editing are suitable therapeutic targets for ALS. Gene therapy has recently emerged as a new therapeutic opportunity for many heretofore incurable diseases, and RNA editing dysregulation can be a target for gene therapy; therefore, we reviewed neurological diseases associated with dysregulated RNA editing and a new therapeutic approach targeting dysregulated RNA editing, especially one that is effective in ALS.

scholarly journals Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination

2018 ◽  
Vol 115 (46) ◽  
pp. E10941-E10950 ◽  
Author(s):  
Jia Wang ◽  
Wan Yun Ho ◽  
Kenneth Lim ◽  
Jia Feng ◽  
Greg Tucker-Kellogg ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Motor Neurons ◽  
Oligodendrocyte Precursor Cells ◽  
Progressive Reduction ◽  
Disease Pathogenesis ◽  
Neuromuscular Synapses ◽  
Oligodendrocyte Precursor ◽  
Early Lethality ◽  
Lateral Sclerosis

TDP-43 aggregates in neurons and glia are the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), raising the possibility of glial damage in the disease pathogenesis. However, the normal physiological functions of TDP-43 in glia are largely unknown. To address how TDP-43 may be required for oligodendroglial functions we selectively deleted TDP-43 in mature oligodendrocytes in mice. Although mice with TDP-43 deleted in oligodendrocytes are born in an expected Mendelian ratio, they develop progressive neurological phenotypes leading to early lethality accompanied by a progressive reduction in myelination. The progressive myelin reduction is likely due to a combination of the cell-autonomous RIPK1-mediated necroptosis of mature oligodendrocytes and the TDP-43–dependent reduction in the expression of myelin genes. Strikingly, enhanced proliferation of NG2-positive oligodendrocyte precursor cells within the white matter, but not the gray matter, was able to replenish the loss of mature oligodendrocytes, indicating an intrinsic regeneration difference between the gray and white matter oligodendrocytes. By contrast, there was no loss of spinal cord motor neurons and no sign of denervation at the neuromuscular synapses. Taken together, our data demonstrate that TDP-43 is indispensable for oligodendrocyte survival and myelination, and loss of TDP-43 in oligodendrocytes exerts no apparent toxicity on motor neurons.

scholarly journals Accelerated Early Progression of Amyotrophic Lateral Sclerosis over the COVID-19 Pandemic

2021 ◽  
Vol 11 (10) ◽  
pp. 1291
Author(s):  
Fabiola De Marchi ◽  
Chiara Gallo ◽  
Maria Francesca Sarnelli ◽  
Ilaria De Marchi ◽  
Massimo Saraceno ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurological Diseases ◽  
Diagnostic Delay ◽  
P Value ◽  
First Year ◽  
Non Invasive Ventilation ◽  
Multidisciplinary Model ◽  
The Impact ◽  
Lateral Sclerosis

During the COVID-19 pandemic and the related lockdowns, outpatient follow-up visits for patients with chronic neurological diseases have been suspended. Managing people affected by amyotrophic lateral sclerosis (ALS) has become highly complicated, leaving patients without the standard multidisciplinary follow-up. This study aimed to analyze the impact of the COVID-19 lockdown on ALS disease progression. We compared the clinical data and progression in the first year following diagnosis for patients who received ALS diagnosis during 2020 (G20, N = 34), comparing it with a group of diagnosed in 2018 (G18, N = 31). Both groups received a comparable multidisciplinary model of care in our Tertiary Expert ALS Centre, Novara, Italy. The monthly rate of ALSFRS-R decline during the lockdown was significantly increased in G20 compared to G18 (1.52 ± 2.69 vs. 0.76 ± 0.56; p-value: 0.005). In G20, 47% required non-invasive ventilation (vs. 32% of G18). Similarly, in G20, 35% of patients died vs. 19% of patients in G18 (p-value: 0.01). All results were corrected for gender, age, site of onset, and diagnostic delay. Several factors can be implicated in making ALS more severe, with a faster progression, such as reduced medical evaluations and the possibility of therapeutic changes, social isolation, and rehabilitation therapy suspension.

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