scholarly journals ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

2019 ◽  
Vol 20 (20) ◽  
pp. 5151 ◽  
Author(s):  
Norante ◽  
Peggion ◽  
Rossi ◽  
Martorana ◽  
De Mario ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Nervous System Function ◽  
Serca Pump ◽  
Selective Death ◽  
First Time ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis

2008 ◽  
Vol 36 (6) ◽  
pp. 1322-1328 ◽  
Author(s):  
Willianne I.M. Vonk ◽  
Leo W.J. Klomp
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Transition Metals ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Sod1 Gene ◽  
Brain And Spinal Cord ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for ALS.

scholarly journals Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yasuhiro Kosuge ◽  
Erina Kaneko ◽  
Hiroshi Nango ◽  
Hiroko Miyagishi ◽  
Kumiko Ishige ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neurons ◽  
Motor Performance ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Bidens Pilosa ◽  
Neuronal Marker ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

scholarly journals Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ching Serena Kao ◽  
Rebekah van Bruggen ◽  
Jihye Rachel Kim ◽  
Xiao Xiao Lily Chen ◽  
Cadia Chan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Motor Neurons ◽  
Neuronal Degeneration ◽  
Early Stage ◽  
Motor Impairment ◽  
Preclinical Research ◽  
Cell Degeneration ◽  
Promising Tool ◽  
Lateral Sclerosis

Abstract A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

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.

Voltage-Dependent Sodium Channels in Spinal Cord Motor Neurons Display Rapid Recovery From Fast Inactivation in a Mouse Model of Amyotrophic Lateral Sclerosis

2006 ◽  
Vol 96 (6) ◽  
pp. 3314-3322 ◽  
Author(s):  
Cristina Zona ◽  
Massimo Pieri ◽  
Irene Carunchio
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Mouse Model ◽  
Sodium Channels ◽  
Motor Neurons ◽  
Fast Inactivation ◽  
Patch Clamp Recording ◽  
Voltage Dependent ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly93→Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na+ currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na+ channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3–48 h) and concentrations (5–500 μM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.

scholarly journals Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

2021 ◽  
Author(s):  
Phan H. Truong ◽  
Peter J. Crouch ◽  
James B. W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

AbstractMotor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

Otolaryngologist’s role in the diagnosis of amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (2) ◽  
pp. e234504
Author(s):  
Joana Borges Costa ◽  
Diogo Pereira ◽  
Delfim Duarte ◽  
Miguel Viana
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Clinical Presentation ◽  
Late Onset ◽  
History Of ◽  
Dysarthric Speech ◽  
Selective Death ◽  
Hypernasal Voice ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and late-onset fatal neurodegenerative disease characterised by selective death of motor neurons. The aetiology of ALS is still unknown and it is extremely heterogeneous in genetics and clinical presentation, being the respiratory failure the usual cause of death. We describe a case of a 61-year-old male patient referred to the otolaryngology consultation for a 6-month history of progressive solid dysphagia and dysphonia. The patient presented several voice alterations such as a dysarthric speech with hypernasal voice which evoked the hypothesis of a neuromuscular disease. That patient was observed by a neurologist and was submitted to an electromyography that confirmed the ALS diagnosis. This case highlights the key role of otolaryngologists in the diagnosis of ALS, in a way that many patients with a bulbar ALS form are initially studied by an otolaryngologist.

scholarly journals Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (20) ◽  
pp. 11224
Author(s):  
Thibaut Burg ◽  
Elisabeth Rossaert ◽  
Matthieu Moisse ◽  
Philip Van Damme ◽  
Ludo Van Den Bosch
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Lipid Metabolism ◽  
Mouse Model ◽  
Histone Deacetylase ◽  
Neurodegenerative Disorder ◽  
Lipid Homeostasis ◽  
Hdac Inhibition ◽  
Histone Deacetylase Inhibition ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.

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