scholarly journals Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lin Bai ◽  
Yafei Wang ◽  
Jia Huo ◽  
Shuai Li ◽  
Ya Wen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Autophagic Flux ◽  
Disease Phenotype ◽  
Simvastatin Treatment ◽  
Previous Evidence ◽  
Ischemic Diseases ◽  
Coa Reductase ◽  
Cancer And Inflammation ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1G93A cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1G93A mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1G93A mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1G93A mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.

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.

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.

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 Spinal cord microglia in health and disease

Acta Naturae ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 4-17
Author(s):  
Elena Kolos ◽  
Dmitry Korzhevsky
Keyword(s):  
Spinal Cord ◽  
Experimental Studies ◽  
Experimental Models ◽  
Specific Marker ◽  
Marker Proteins ◽  
Health And Disease ◽  
And Function ◽  
Lateral Sclerosis

The review summarizes data of recent experimental studies on spinal microglia, the least explored cells of the spinal cord. It focuses on the origin and function of microglia in mammalian spinal cord embryogenesis. The main approaches to the classification of microgliocytes based on their structure, function, and immunophenotypic characteristics are analyzed. We discuss the results of studies conducted on experimental models of spinal cord diseases such as multiple sclerosis, amyotrophic lateral sclerosis, systemic inflammation, and some others, with special emphasis on the key role of microglia in the pathogenesis of these diseases. The review highlights the need to detect the new microglia-specific marker proteins expressed at all stages of ontogeny. New sensitive and selective microglial markers are necessary in order to improve identification of spinal cord microgliocytes in normal and pathological conditions. Possible morphometric methods to assess the functional activity of microglial cells are presented.

scholarly journals Autophagy in Neurotrauma: Good, Bad, or Dysregulated

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 693 ◽  
Author(s):  
Junfang Wu ◽  
Marta M. Lipinski
Keyword(s):  
Spinal Cord ◽  
Membrane Damage ◽  
Strong Support ◽  
Experimental Models ◽  
Autophagic Flux ◽  
Central Nervous Systems ◽  
Autophagic Degradation ◽  
Degradation Activity ◽  
Cellular Components

Autophagy is a physiological process that helps maintain a balance between the manufacture of cellular components and breakdown of damaged organelles and other toxic cellular constituents. Changes in autophagic markers are readily detectable in the spinal cord and brain following neurotrauma, including traumatic spinal cord and brain injury (SCI/TBI). However, the role of autophagy in neurotrauma remains less clear. Whether autophagy is good or bad is under debate, with strong support for both a beneficial and detrimental role for autophagy in experimental models of neurotrauma. Emerging data suggest that autophagic flux, a measure of autophagic degradation activity, is impaired in injured central nervous systems (CNS), and interventions that stimulate autophagic flux may provide neuroprotection in SCI/TBI models. Recent data demonstrating that neurotrauma can cause lysosomal membrane damage resulting in pathological autophagosome accumulation in the spinal cord and brain further supports the idea that the impairment of the autophagy–lysosome pathway may be a part of secondary injury processes of SCI/TBI. Here, we review experimental work on the complex and varied responses of autophagy in terms of both the beneficial and detrimental effects in SCI and TBI models. We also discuss the existing and developing therapeutic options aimed at reducing the disruption of autophagy to protect the CNS after injuries.

Acute spinal cord injury in rats should target activated autophagy

2014 ◽  
Vol 20 (5) ◽  
pp. 568-577 ◽  
Author(s):  
Hongping Hou ◽  
Lihai Zhang ◽  
Licheng Zhang ◽  
Peifu Tang
Keyword(s):  
Electron Microscopy ◽  
Spinal Cord ◽  
Caspase 3 ◽  
Potential Role ◽  
Autophagic Flux ◽  
Autophagosome Formation ◽  
Expression Levels ◽  
Cord Injury ◽  
Microscopy Images

Object Autophagy is a cellular mechanism of maintaining balance between protein synthesis and degradation; the latter can be induced by starvation and neurodegenerative disease. Spinal cord injury (SCI) induces necrosis and apoptosis. Autophagic flux has not yet been defined, especially the potential role of autophagy in relation to apoptosis in different tissue cells. The object of this study was to investigate the occurrence of autophagic flux and the potential role of autophagy and apoptosis post-SCI in rats. Methods Following creation of SCI in rats, activation of autophagic flux was detected at the protein (LC3, beclin1, and p62) and mRNA (beclin1) levels and on electron microscopy images. Distribution of LC3, colocalization of activated caspase-3, and changes in expression levels of bcl-2 and Bax were assessed to investigate the potential role of autophagy and apoptosis. Sprague-Dawley rats were used, and T9–10 hemitransection was performed. Expression levels of LC3, beclin1, p62, bcl-2, and Bax were assessed by Western blot analysis, and beclin1 mRNA levels were assessed by reverse transcription–polymerase chain reaction. Distribution of LC3 and colocalization of activated caspase-3 were analyzed by immunohistochemistry. Autophagosome formation was investigated by electron microscopy. Results The authors found a dramatic elevation in LC3 and beclin1 levels near the scar region. Using double staining, they observed that upregulation of LC3 started at 4 hours in neurons and at 3 days in astrocytes after SCI. Confocal images indicated that the percentage of neurons with apoptosis was reduced, while the percentage of astrocytes with apoptosis was high at 4 hours, 8 hours, and 1 day post-SCI but decreased sharply at 3 days. Electron microscopy images provided evidence of autophagosome formation. Elimination of p62 indicated occurrence of autophagic flux. Expression levels of bcl-2 and Bax were increased and decreased, respectively, near the injury site. Conclusions The results of this research demonstrated that autophagic flux is activated after SCI. Potentially, inhibition of apoptosis could be a target to promote neural recovery.

Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice

2013 ◽  
Vol 35 (8) ◽  
pp. 1199-1207 ◽  
Author(s):  
Shanshan Wang ◽  
Yingjun Guan ◽  
Yanchun Chen ◽  
Xiaojin Li ◽  
Caixia Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Lateral Sclerosis

scholarly journals The Role of Substance P in Neurodegenerative Diseases

2020 ◽  
Author(s):  
Atefeh Ghahremanloo ◽  
Fariba Mohammadi ◽  
Seyed Isaac Hashemy
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Substance P ◽  
Neurodegenerative Disorders ◽  
Review Article ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Abstract- Tachykinins (TKs) are a family of neuropeptides widely distributed in the human body, especially in the nervous system. TKs have exhibited both neuroprotective and neurodegenerative properties in the central nervous system (CNS) and spinal cord. Also, several studies have shown that substance P (SP), as a pioneering neuropeptide of the TK family, is engaged in the pathogenesis of neurodegenerative disorders (NDs), such as Alzheimer disease, Multiple Sclerosis, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. However, a huge body of information available about the level of SP in NDs demonstrates that SP and its receptors might be prognostic or diagnostic factors for NDs. The present review article summarizes the roles of TKs in common neurodegenerative disorders.

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