scholarly journals Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism

2020 ◽  
Author(s):  
Tanya S. McDonald ◽  
Vinod Kumar ◽  
Jenny N. Fung ◽  
Trent M. Woodruff ◽  
John D. Lee
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Disease Stage ◽  
Metabolic Disturbances ◽  
Symptomatic Disease ◽  
Lateral Sclerosis

AbstractMetabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS), however the molecular events that drive energy imbalances in ALS are not completely understood. In this study we aimed to elucidate deficits in energy homeostasis in the SOD1G93A mouse model of ALS. We identified that SOD1G93A mice at mid-symptomatic disease stage have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signalling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilised efficiently in SOD1G93A mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1G93A mice, which is linked to an increase in insulin-independent glucose uptake and a disturbance in glucagon sensitivity, suggesting glucagon secretion and signalling could be potential therapeutic targets for ALS.

scholarly journals Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

2020 ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Luc Dupuis ◽  
Tobias Boeckers ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Metabolic Phenotype ◽  
Metabolic Disturbances ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractIncreased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.Significance statementWe provide a circuit perspective of the recently identified and medically relevant hyper-metabolic phenotype of Amyotrophic Lateral Sclerosis. We demonstrate the selective involvement of orbitofrontal, insular and motor cortex projections to hypothalamus in murine ALS models and in human patients. The enhanced pipeline for large-scale registration, segmentation projections mapping, the identification of new circuits target of neurodegeneration, and the relevance of these circuits in metabolic disturbances make this work relevant not only for the investigation of ALS but also for other neurodegenerative disease as well as for all conditions characterized by systemic energy imbalances.

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 Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 15 ◽  
pp. 263310552095730 ◽  
Author(s):  
Mara-Luciana Floare ◽  
Scott P. Allen
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Metabolic Dysfunction ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Reading Frame ◽  
Fused In Sarcoma ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).

scholarly journals Metabolic Changes in an Animal Model of Amyotrophic Lateral Sclerosis Evaluated by [18F]-FDG Positron Emission Tomography

2021 ◽  
Author(s):  
Bruno Lima Giacobbo ◽  
Tomás Mediavilla ◽  
Daniel J. Marcellino ◽  
Fahad Sultan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Animal Models ◽  
Glucose Uptake ◽  
Metabolic Activity ◽  
Neurodegenerative Disorder ◽  
Metabolic Changes ◽  
Whole Brain ◽  
Fdg Uptake ◽  
The Brain ◽  
Lateral Sclerosis

Abstract Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function and eventual death. Genetic background account for 10% of all ALS cases and several genes are associated with the onset and progression of disease in humans. Studies in humans have observed differences in glucose uptake in the brain using [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG), however, no studies in animal models of ALS have been performed on the matter. The goal of this study was to evaluate ALS-related metabolic changes in [ 18 F]-FDG uptake within the brain of transgenic mice that express a mutated human SOD1 gene (hSOD1 G93A ). Methods: Animals were genotyped for the hSOD1 G93A mutation using PCR and divided into groups according to the presence (ALS) or absence (WT) of transgene. When transgenic ALS mice started to develop motor impairment, animals were scanned for 10 minutes using PET [ 18 F]-FDG. Gender-matched WT animals were scanned at similar ages as ALS animals. The images were coregistered to an [ 18 F]-FDG template and both the standardized uptake value (SUV) and the ratio of radioactivity of target regions to the mean radioactivity of the whole brain (TRR) were calculated for 19 volumes of interest. Results: Significant effects of genotype were observed in the overall metabolic activity assessed by both SUV and ratio-to-whole brain, in which ALS mice presented with lower metabolic activity in several regions when compared with age- and gender-matched WT mice. These changes were more pronounced in hippocampus, thalamus, and midbrain. A significant effect of gender was found in the SUV of several of the regions evaluated, although these gender-related differences were not observed after normalization to the whole-brain uptake. Conclusions: The differences in [ 18 F]-FDG uptake in the brain of ALS SOD1 animals suggest a significant metabolic impairment in several of the regions evaluated. Such differences might be due to a general hypometabolic state of the animals when compared to their WT littermates. These findings suggest a possible influence of disease in brain glucose uptake and open new possibilities for the understanding of the ALS pathophysiology using animal models, as well as a possible prognostic usage of [ 18 F]-FDG in ALS in humans.

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.

Automated Acoustic Analysis of Oral Diadochokinesis to Assess Bulbar Motor Involvement in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 63 (1) ◽  
pp. 59-73 ◽  
Author(s):  
Panying Rong
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Acoustic Analysis ◽  
Speaking Rate ◽  
Disease Stage ◽  
Healthy Controls ◽  
Tongue Movement ◽  
Major Barrier ◽  
Syllable Repetition ◽  
Oral Diadochokinesis ◽  
Lateral Sclerosis

Purpose The purpose of this article was to validate a novel acoustic analysis of oral diadochokinesis (DDK) in assessing bulbar motor involvement in amyotrophic lateral sclerosis (ALS). Method An automated acoustic DDK analysis was developed, which filtered out the voice features and extracted the envelope of the acoustic waveform reflecting the temporal pattern of syllable repetitions during an oral DDK task (i.e., repetitions of /tɑ/ at the maximum rate on 1 breath). Cycle-to-cycle temporal variability (cTV) of envelope fluctuations and syllable repetition rate (sylRate) were derived from the envelope and validated against 2 kinematic measures, which are tongue movement jitter (movJitter) and alternating tongue movement rate (AMR) during the DDK task, in 16 individuals with bulbar ALS and 18 healthy controls. After the validation, cTV, sylRate, movJitter, and AMR, along with an established clinical speech measure, that is, speaking rate (SR), were compared in their ability to (a) differentiate individuals with ALS from healthy controls and (b) detect early-stage bulbar declines in ALS. Results cTV and sylRate were significantly correlated with movJitter and AMR, respectively, across individuals with ALS and healthy controls, confirming the validity of the acoustic DDK analysis in extracting the temporal DDK pattern. Among all the acoustic and kinematic DDK measures, cTV showed the highest diagnostic accuracy (i.e., 0.87) with 80% sensitivity and 94% specificity in differentiating individuals with ALS from healthy controls, which outperformed the SR measure. Moreover, cTV showed a large increase during the early disease stage, which preceded the decline of SR. Conclusions This study provided preliminary validation of a novel automated acoustic DDK analysis in extracting a useful measure, namely, cTV, for early detection of bulbar ALS. This analysis overcame a major barrier in the existing acoustic DDK analysis, which is continuous voicing between syllables that interferes with syllable structures. This approach has potential clinical applications as a novel bulbar assessment.

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