scholarly journals BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (22) ◽  
pp. 12533
Author(s):  
Marta Gómez-Almería ◽  
Sonia Burgaz ◽  
Carlos Costas-Insua ◽  
Carmen Rodríguez-Cueto ◽  
Irene Santos-García ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Cb1 Receptor ◽  
Mutant Mice ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Neurological Score ◽  
6 Hydroxydopamine ◽  
Lateral Sclerosis

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.

scholarly journals Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yafa Fetfet Malada Edelstein ◽  
Yulia Solomonov ◽  
Nurit Hadad ◽  
Leenor Alfahel ◽  
Adrian Israelson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Dependent Manner ◽  
Mutant Sod1 ◽  
Over Expression ◽  
Cytosolic Phospholipase ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.

Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1G93A transgenic mice, an experimental model of amyotrophic lateral sclerosis

2018 ◽  
Vol 157 ◽  
pp. 217-226 ◽  
Author(s):  
Carmen Rodríguez-Cueto ◽  
Irene Santos-García ◽  
Laura García-Toscano ◽  
Francisco Espejo-Porras ◽  
MLuz Bellido ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Experimental Model ◽  
Neuroprotective Effects ◽  
Lateral Sclerosis ◽  
Quinone Derivative

A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis

1995 ◽  
Vol 73 (9-10) ◽  
pp. 593-597 ◽  
Author(s):  
Jean-Pierre Julien
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Axonal Transport ◽  
Motor Neurons ◽  
Intracellular Transport ◽  
Late Onset ◽  
Cytoskeletal Proteins ◽  
H Gene ◽  
Abnormal Accumulation ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.Key words: amyotrophic lateral sclerosis, neurofilaments, transgenic mice, axonal transport.

Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice

2005 ◽  
Vol 1045 (1-2) ◽  
pp. 185-198 ◽  
Author(s):  
Silvina S. Holasek ◽  
Thomas M. Wengenack ◽  
Karunya K. Kandimalla ◽  
Carolina Montano ◽  
Dawn M. Gregor ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Map Kinase ◽  
Motor Neurons ◽  
Cortical Motor ◽  
Lateral Sclerosis

Riluzole for the treatment of amyotrophic lateral sclerosis

2020 ◽  
Vol 10 (6) ◽  
pp. 343-355
Author(s):  
Yuji Saitoh ◽  
Yuji Takahashi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Clinical Practice ◽  
Physical Properties ◽  
Motor Neurons ◽  
Glutamatergic Neurotransmission ◽  
Neuroprotective Effects ◽  
Free Survival ◽  
The Us ◽  
Us Fda ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the death of motor neurons. Riluzole is a benzothiazole derivative that blocks glutamatergic neurotransmission in the CNS, which is thought to exert neuroprotective effects. Riluzole was approved by the US FDA in 1995 as the first drug to treat ALS. Although riluzole is generally safe and well tolerated in clinical practice, its efficacy in ALS is modest, prolonging tracheostomy-free survival by only 2–3 months. In this article, we will first provide an overview of the ALS field, followed by a discussion of riluzole regarding its physical properties; pharmacology; clinical efficacy in ALS; safety and tolerability; and recommended administration.

Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis

2005 ◽  
Vol 196 (2) ◽  
pp. 235-243 ◽  
Author(s):  
Richelle Hemendinger ◽  
Jay Wang ◽  
Saafan Malik ◽  
Rafal Persinski ◽  
Jane Copeland ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Sertoli Cells ◽  
Survival Of Motor Neurons ◽  
Lateral Sclerosis

Ginsenoside Re Attenuates Neuroinflammation in a Symptomatic ALS Animal Model

2016 ◽  
Vol 44 (02) ◽  
pp. 401-413 ◽  
Author(s):  
Mudan Cai ◽  
Eun Jin Yang
Keyword(s):  
Spinal Cord ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Neuroprotective Effects ◽  
Respiratory Dysfunction ◽  
Ginsenoside Re ◽  
Protein Levels ◽  
Inflammatory Proteins ◽  
Tlr4 Signaling Pathway ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, which cause paralysis and respiratory dysfunction. There is currently no permanently effective drug for patients with ALS. Ginsenoside Re (G-Re), one of the most active ingredients of ginseng, has pharmacological activities that affect a number of targets. To investigate the effects of G-Re on neuroinflammation, we used G-Re (2.5[Formula: see text][Formula: see text]g/g) at the Joksamni acupressure point (ST36) once every other day for one week. To evaluate G-Re function in symptomatic human-superoxide dismutase 1 (hSOD1[Formula: see text] transgenic mice, immunohistochemistry and Western blot analysis were performed with the spinal cord of symptomatic hSOD1G93A transgenic mice. Here, we report that G-Re exhibits potent neuroprotective effects against neuroinflammation in a murine model of ALS. G-Re treatment reduced the loss of motor neurons and active-microglia-related expression of Iba-1 in the spinal cord of symptomatic hSOD1G93A transgenic mice. In addition, compared with age-matched hSOD1G93A mice, G-Re-treated hSOD1G93A mice showed a significant reduction in expression of pro-inflammatory proteins such as CD14 and TNF-[Formula: see text] protein related to TLR4 signaling pathway. G-Re administration also led to a decrease in cell death-related phospho-p38 protein levels, and had an antioxidative effect by reducing HO1 expression. Together, our data suggest that G-Re could have potent anti-neuroinflammatory effects on ALS by inhibiting the TLR4 pathway.

scholarly journals A neurotoxic peripherin splice variant in a mouse model of ALS

2003 ◽  
Vol 160 (6) ◽  
pp. 939-949 ◽  
Author(s):  
Janice Robertson ◽  
Mohammad M. Doroudchi ◽  
Minh Dang Nguyen ◽  
Heather D. Durham ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Splice Variants ◽  
Superoxide Dismutase 1 ◽  
Specific Antibodies ◽  
Axonal Spheroids ◽  
Familial Als ◽  
Nif Proteins ◽  
Lateral Sclerosis

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

Exploring molecular approaches in Amyotrophic lateral sclerosis: Drug targets from clinical and pre-clinical findings

2020 ◽  
Vol 13 ◽  
Author(s):  
Mamtaj Alam ◽  
Rajeshwar Kumar Yadav ◽  
Elizabeth Minj ◽  
Aarti Tiwari ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Drug Targets ◽  
Therapeutic Index ◽  
Experimental Models ◽  
Clinical Findings ◽  
Adenyl Cyclase ◽  
Molecular Approaches ◽  
Pharmacologically Active ◽  
Lateral Sclerosis

: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterised by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age included impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% beyond 10 years of age. The limited intervention of pharmacologically active compounds that are used clinically is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, current review specially targeted in the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with up-regulation of intracellular adenyl cyclase/cAMP/CREB and mitochondrial-ETC coenzyme-Q10 activation as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

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