scholarly journals Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression

2019 ◽  
Vol 20 (18) ◽  
pp. 4552 ◽  
Author(s):  
Tiziana Bonifacino ◽  
Claudia Rebosio ◽  
Francesca Provenzano ◽  
Carola Torazza ◽  
Matilde Balbi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Metabotropic Glutamate Receptors ◽  
Disease Stage ◽  
Spinal Cord Tissue ◽  
Mouse Spinal Cord ◽  
Sod1g93a Mice ◽  
Group I ◽  
Sod1g93a Mouse ◽  
Lateral Sclerosis

Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1G93A mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1G93A mice. The mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) concentration dependently stimulated the release of [3H]d-Aspartate ([3H]d-Asp), which was comparable in 30- and 60-day-old wild type mice and SOD1G93A mice. At variance, [3H]d-Asp release was significantly augmented in 90-day-old SOD1G93A mice and both mGluR1 and mGluR5 were involved. The 3,5-DHPG-induced [3H]d-Asp release was exocytotic, being of vesicular origin and mediated by intra-terminal Ca2+ release. mGluR1 and mGluR5 expression was increased in Glu spinal cord axon terminals of 90-day-old SOD1G93A mice, but not in the whole axon terminal population. Interestingly, mGluR1 and mGluR5 were significantly augmented in total spinal cord tissue already at 60 days. Thus, function and expression of group I mGluRs are enhanced in the early-symptomatic SOD1G93A mouse spinal cord, possibly participating in excessive Glu transmission and supporting their implication in ALS. Please define all abbreviations the first time they appear in the abstract, the main text, and the first figure or table caption.

Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue

Neuroscience ◽  
2011 ◽  
Vol 179 ◽  
pp. 233-243 ◽  
Author(s):  
M. Casula ◽  
A.M. Iyer ◽  
W.G.M. Spliet ◽  
J.J. Anink ◽  
K. Steentjes ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Spinal Cord Tissue ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
Lateral Sclerosis

scholarly journals Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis

2018 ◽  
Vol 115 (32) ◽  
pp. 8209-8214 ◽  
Author(s):  
Danilo B. Medinas ◽  
Pablo Rozas ◽  
Francisca Martínez Traub ◽  
Ute Woehlbier ◽  
Robert H. Brown ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Endoplasmic Reticulum ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Spinal Cord Tissue ◽  
Wild Type ◽  
Sporadic Als ◽  
Lateral Sclerosis

Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1WT) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1WT species are unknown. We analyzed aberrant human SOD1WT species over the lifetime of transgenic mice and found the accumulation of disulfide–cross-linked high–molecular-weight SOD1WT aggregates during aging. Subcellular fractionation of spinal cord tissue and protein overexpression in NSC-34 motoneuron-like cells revealed that endoplasmic reticulum (ER) localization favors oxidation and disulfide-dependent aggregation of SOD1WT. We established a pharmacological paradigm of chronic ER stress in vivo, which recapitulated SOD1WTaggregation in young transgenic mice. These species were soluble in nondenaturing detergents and did not react with a SOD1 conformation-specific antibody. Interestingly, SOD1WT aggregation under ER stress correlated with astrocyte activation in the spinal cord of transgenic mice. Finally, the disulfide–cross-linked SOD1WT species were also found augmented in spinal cord tissue of sALS patients, correlating with the presence of ER stress markers. Overall, this study suggests that ER stress increases the susceptibility of SOD1WT to aggregate during aging, operating as a possible risk factor for developing ALS.

scholarly journals Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 760
Author(s):  
Merina Varghese ◽  
Wei Zhao ◽  
Kyle J. Trageser ◽  
Giulio M. Pasinetti
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Whole Body ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Actin Promoter ◽  
Sod1g93a Mouse ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1α has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1α as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1α under a neuron-specific enolase (NSE) promoter. As pharmacological intervention targeting PGC-1α would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1α is beneficial in a SOD1G93A mouse model, by generating transgenic mice with PGC-1α transgene expression driven by an actin promoter. Actin-PGC-1α expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1α, wild-type, actin-PGC-1α, SOD1G93A, and actin-PGC-1α/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1α did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1α relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons.

scholarly journals Proteomic characterization of lipid raft proteins in amyotrophic lateral sclerosis mouse spinal cord

FEBS Journal ◽  
2009 ◽  
Vol 276 (12) ◽  
pp. 3308-3323 ◽  
Author(s):  
Jianjun Zhai ◽  
Anna-Lena Ström ◽  
Renee Kilty ◽  
Priya Venkatakrishnan ◽  
James White ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Lipid Raft ◽  
Mouse Spinal Cord ◽  
Lateral Sclerosis

Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue

2003 ◽  
Vol 55 (2) ◽  
pp. 221-235 ◽  
Author(s):  
Jenny S. Henkel ◽  
Joseph I. Engelhardt ◽  
László Siklós ◽  
Ericka P. Simpson ◽  
Seung H. Kim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Dendritic Cells ◽  
Spinal Cord Tissue ◽  
Activated Microglia ◽  
Lateral Sclerosis
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