scholarly journals Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Michael Sloth Trabjerg ◽  
Anne Skøttrup Mørkholt ◽  
Jacek Lichota ◽  
Michal Krystian Egelund Oklinski ◽  
Dennis Christian Andersen ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Mutant Mouse ◽  
Experimental Models ◽  
Metabolic Shift ◽  
Carnitine Palmitoyl Transferase ◽  
Autoimmune Encephalomyelitis ◽  
Cns Diseases ◽  
Regulatory Systems ◽  
Systemic Model ◽  
Lateral Sclerosis

Abstract The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.

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.

scholarly journals Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.

2021 ◽  
Author(s):  
Mhoriam Ahmed ◽  
Charlotte Spicer ◽  
Jasmine Harley ◽  
Nikolaj Petersen ◽  
Paul Taylor ◽  
...  
Keyword(s):  
Heat Shock ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Pathological Changes ◽  
Beneficial Effects ◽  
Disease Spectrum ◽  
Shock Response ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now widely considered to be part of a disease spectrum with the identification of common pathological features and genetic causes. However, despite these advances, there remains no effective therapy for these conditions. In this study we demonstrate that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype. Moreover, the beneficial effects of arimoclomol are seen in both fibroblasts and iPSC-derived motor neurons from patients. Importantly, we show the pathological changes targeted by arimoclomol in our experimental models are present in post-mortem FTD patient tissue. Together with previous data demonstrating the efficacy of arimoclomol in SOD1-ALS models, our findings suggest that arimoclomol may have therapeutic potential not only in non-SOD1 ALS but also for the treatment of FTD.

scholarly journals Protocol for a systematic review and meta-analysis of experimental models of amyotrophic lateral sclerosis

2016 ◽  
Vol 3 (2) ◽  
pp. e00023
Author(s):  
J. M. Gregory ◽  
F. M. Waldron ◽  
T. Soane ◽  
L. Fulton ◽  
D. Leighton ◽  
...  
Keyword(s):  
Systematic Review ◽  
Amyotrophic Lateral Sclerosis ◽  
Meta Analysis ◽  
Experimental Models ◽  
Lateral Sclerosis

scholarly journals Viral Delivery of Antioxidant Genes as a Therapeutic Strategy in Experimental Models of Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 21 (8) ◽  
pp. 1486-1496 ◽  
Author(s):  
Aikaterini Nanou ◽  
Adrian Higginbottom ◽  
Chiara F Valori ◽  
Matthew Wyles ◽  
Ke Ning ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Strategy ◽  
Experimental Models ◽  
Antioxidant Genes ◽  
Lateral Sclerosis

Iron Regulatory Proteins in Systemic Iron Metabolism and Erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Matthias W. Hentze
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Mutant Mouse ◽  
Conflicts Of Interest ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Regulatory Systems ◽  
Biology I ◽  
Mouse Lines

Abstract Abstract SCI-22 Imbalances of iron homeostasis account for some of the most common human diseases. Pathologies can result from both iron deficiency or overload. The hepcidin/ferroportin and the IRE/IRP regulatory systems balance systemic and cellular iron metabolism, respectively, and understanding their points of intersection and crosstalk represents a major challenge in iron biology. I will discuss an emerging picture from studies with different mutant mouse lines according to which the “cellular” IRE/IRP system determines “set points” via its targets (including ferroportin and HIF2α). These are then subject to modulation via hepcidin in response to systemic cues. Disclosures: No relevant conflicts of interest to declare.

Folate receptor-targeted aminopterin therapy is highly effective and specific in experimental models of autoimmune uveitis and autoimmune encephalomyelitis

2014 ◽  
Vol 150 (1) ◽  
pp. 64-77 ◽  
Author(s):  
Yingjuan Lu ◽  
Kristin N. Wollak ◽  
Vicky A. Cross ◽  
Elaine Westrick ◽  
Leroy W. Wheeler ◽  
...  
Keyword(s):  
Folate Receptor ◽  
Experimental Models ◽  
Autoimmune Encephalomyelitis ◽  
Autoimmune Uveitis ◽  
Highly Effective

scholarly journals Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Núria Gaja-Capdevila ◽  
Neus Hernández ◽  
Xavier Navarro ◽  
Mireia Herrando-Grabulosa
Keyword(s):  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Neuromuscular Function ◽  
Experimental Models ◽  
Autophagic Flux ◽  
Sigma 1 Receptor ◽  
Improve Motor Function ◽  
Sigma 1 ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1G93A mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1G93A mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1G93A mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.

scholarly journals Increased Cerebral Tff1 Expression in Two Murine Models of Neuroinflammation

2016 ◽  
Vol 39 (6) ◽  
pp. 2287-2296 ◽  
Author(s):  
Eva B Znalesniak ◽  
Ting Fu ◽  
Karina Guttek ◽  
Ulrike Händel ◽  
Dirk Reinhold ◽  
...  
Keyword(s):  
Expression Profiling ◽  
Biological Effects ◽  
Transcript Level ◽  
Experimental Models ◽  
Secretory Product ◽  
Murine Models ◽  
Autoimmune Encephalomyelitis ◽  
Interleukin 17A ◽  
Apoptotic Effect ◽  
Factor Α

Background/Aims: The trefoil factor family (TFF) peptide TFF1 is a typical secretory product of the gastric mucosa and a very low level of expression occurs in nearly all regions of the murine brain. TFF1 possesses a lectin activity and binding to a plethora of transmembrane glycoproteins could explain the diverse biological effects of TFF1 (e.g., anti-apoptotic effect). It was the aim to test whether TFF expression is changed during neuroinflammation. Methods: Expression profiling was performed using semi-quantitative RT-PCR analyses in two murine models of neuroinflammation, i.e. Toxoplasma gondii-induced encephalitis and experimental autoimmune encephalomyelitis (EAE), the latter being the most common animal model of multiple sclerosis. Tff1 expression was also localized using RNA in situ hybridization histochemistry. Results: We report for the first time on a significant transcriptional induction in cerebral Tff1 expression in both T. gondii-induced encephalitis and EAE. In contrast, Tff2 and Tff3 expression were not altered. Tff1 transcripts were predominantly localized in the internal granular layer of the cerebellum indicating neuronal expression. Furthermore, also glial cells are expected to express Tff1. Characterization of both experimental models by expression profiling (e.g., inflammasome sensors, inflammatory cytokines, microglial marker Iba1, ependymin related protein 1) revealed differences concerning the expression of the inflammasome sensor Nlrp1 and interleukin 17a. Conclusion: The up-regulated expression of Tff1 is probably the result of a complex inflammatory process as its expression is induced by tumor necrosis factor α as well as interleukins 1β and 17. However on the transcript level, Tff1KO mice did not show any significant signs of an altered immune response after infection with T. gondii in comparison with the wild type animals.

scholarly journals Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael Sloth Trabjerg ◽  
Dennis Christian Andersen ◽  
Pam Huntjens ◽  
Kirsten Egelund Oklinski ◽  
Luise Bolther ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mouse Model ◽  
Disease Progression ◽  
Motor Neurons ◽  
High Fat Diet ◽  
High Fat ◽  
Carnitine Palmitoyl Transferase ◽  
Disease Symptoms ◽  
Lateral Sclerosis ◽  
Sod1 G93a Mouse

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS.

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