scholarly journals Little Helpers or Mean Rogue—Role of Microglia in Animal Models of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (3) ◽  
pp. 993
Author(s):  
Hilal Cihankaya ◽  
Carsten Theiss ◽  
Veronika Matschke
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Disease Onset ◽  
Cellular Level ◽  
Chromosome 9 ◽  
Common Denominator ◽  
Vacuolar Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, causing degeneration of both upper and lower motor neurons in the central nervous system (CNS). ALS patients suffer from hyperreflexia, spasticity, paralysis and muscle atrophy and typically die due to respiratory failure 1–5 years after disease onset. In addition to the degeneration of motor neurons on the cellular level, ALS has been associated with neuroinflammation, such as microgliosis. Microglial activation in ALS can either be protective or degenerative to the neurons. Among others, mutations in superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9Orf72), transactive response DNA binding protein (TDP) 43 and vacuolar protein sorting-associated protein 54 (VPS54) genes have been associated with ALS. Here, we describe the dual role and functionality of microglia in four different in vivo ALS models and search for the lowest common denominator with respect to the role of microglia in the highly heterogeneous disease of ALS.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Neuroprotective Role of the Basic Leucine Zipper Transcription Factor NFIL3 in Models of Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 289 (3) ◽  
pp. 1629-1638 ◽  
Author(s):  
So-ichi Tamai ◽  
Keisuke Imaizumi ◽  
Nobuhiro Kurabayashi ◽  
Minh Dang Nguyen ◽  
Takaya Abe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transcription Factor ◽  
Motor Neurons ◽  
Leucine Zipper ◽  
Neuronal Damage ◽  
Disease Onset ◽  
Basic Leucine Zipper ◽  
A Cell ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons. Here we show that the basic leucine zipper transcription factor NFIL3 (also called E4BP4) confers neuroprotection in models of ALS. NFIL3 is up-regulated in primary neurons challenged with neurotoxic insults and in a mouse model of ALS. Overexpression of NFIL3 attenuates excitotoxic neuronal damage and protects neurons against neurodegeneration in a cell-based ALS model. Conversely, reduction of NFIL3 exacerbates neuronal demise in adverse conditions. Transgenic neuronal expression of NFIL3 in ALS mice delays disease onset and attenuates motor axon and neuron degeneration. These results suggest that NFIL3 plays a neuroprotective role in neurons and constitutes a potential therapeutic target for neurodegeneration.

scholarly journals Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis

2021 ◽  
pp. 1-15
Author(s):  
Vasily Vorobyov ◽  
Alexander Deev ◽  
Frank Sengpiel ◽  
Vladimir Nebogatikov ◽  
Aleksey A. Ustyugov
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Neurons ◽  
Primary Motor Cortex ◽  
Beta Activity ◽  
Systemic Injection ◽  
Eeg Spectra ◽  
Electroencephalogram Eeg ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

scholarly journals The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 19 (10) ◽  
pp. 3137 ◽  
Author(s):  
Anna Konopka ◽  
Julie Atkin
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Gene Encoding ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Early Onset Dementia ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.

scholarly journals In Vivo Validation of Bimolecular Fluorescence Complementation (BiFC) to Investigate Aggregate Formation in Amyotrophic Lateral Sclerosis (ALS)

2020 ◽  
Author(s):  
Emily K Don ◽  
Alina Maschirow ◽  
Rowan A W Radford ◽  
Natalie M Scherer ◽  
Andres Vidal-Itriago ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Onset ◽  
Bimolecular Fluorescence Complementation ◽  
Aggregate Formation ◽  
Reporter Protein ◽  
Fluorescent Reporter ◽  
Lateral Sclerosis ◽  
Fluorescence Complementation ◽  
Bimolecular Fluorescence

AbstractAmyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that is characterized by the progressive loss of motor neurons within the spinal cord, brainstem and motor cortex. Although ALS clinically manifests as a heterogeneous disease, with varying disease onset and survival, a unifying feature is the presence of ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, the precise mechanisms linking protein inclusions and aggregation to neuronal loss are currently poorly understood.Bimolecular Fluorescence Complementation (BiFC) takes advantage the association of fluorophore fragments (non-fluorescent on their own) that are attached to an aggregation prone protein of interest. Interaction of the proteins of interest allows for the fluorescent reporter protein to fold into its native state and emit a fluorescent signal. Here, we combined the power of BiFC with the advantages of the zebrafish system to validate, optimize and visualize of the formation of ALS-linked aggregates in real time in a vertebrate model. We further provide in vivo validation of the selectivity of this technique and demonstrate reduced spontaneous self-assembly of the non-fluorescent fragments in vivo by introducing a fluorophore mutation. Additionally, we report preliminary findings on the dynamic aggregation of the ALS-linked hallmark proteins Fus and TDP-43 in their corresponding nuclear and cytoplasmic compartments using BiFC.Overall, our data demonstrates the suitability of this BiFC approach to study and characterize ALS-linked aggregate formation in vivo. Importantly, the same principle can be applied in the context of other neurodegenerative diseases and has therefore critical implications to advance our understanding of pathologies that underlie aberrant protein aggregation.

scholarly journals Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

2015 ◽  
Vol 77 (3-4) ◽  
Author(s):  
B. Chandrasoma ◽  
D. Balfe ◽  
T. Naik ◽  
A. Elsayegh ◽  
M. Lewis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pulmonary Function ◽  
Muscle Weakness ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Disease Onset ◽  
Group Versus ◽  
Combination Methods ◽  
Lateral Sclerosis

Background. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of Amyotrophic Lateral Sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. Methods. Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. Results. There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced(43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p=0.15) and the RV to be higher (157.4% versus 135.9%, P=0.24). Conclusions. ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities.

scholarly journals Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Vartika Mishra ◽  
Diane B. Re ◽  
Virginia Le Verche ◽  
Mariano J. Alvarez ◽  
Alessandro Vasciaveo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Death Receptor ◽  
Cell Interaction ◽  
Type Motor ◽  
Cellular Compartments ◽  
Death Receptor 6 ◽  
Lateral Sclerosis

Abstract Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ligand-mediated interactions between distinct cellular compartments. To test this approach, we selected a model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs) by an unknown mechanism. Our integrative analysis that combines proteomics and regulatory network analysis infers the interaction between astrocyte-released amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. Our results support the usefulness of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS and posit that the proposed methodology is not restricted to this biological context and could be used in a variety of other non-cell-autonomous communication mechanisms.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

scholarly journals Role of PET and SPECT in the Study of Amyotrophic Lateral Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Angelina Cistaro ◽  
Vincenzo Cuccurullo ◽  
Natale Quartuccio ◽  
Marco Pagani ◽  
Maria Consuelo Valentini ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Primary Motor Cortex ◽  
Clinical Laboratory ◽  
Resonance Imaging ◽  
Muscle Paralysis ◽  
Additional Information ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis has been defined as a “heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord.” A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals.

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