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 Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Rami Saad ◽  
Luc Dupuis ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Diffusion Tensor ◽  
Metabolic Dysfunction ◽  
Projection Mapping ◽  
Magnetic Resonance Imaging Mri ◽  
Als Patients

Abstract Background Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

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 Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints

2022 ◽  
Author(s):  
Teresa Cunha-Oliveira ◽  
Marcelo Carvalho ◽  
Vilma Sardão ◽  
Elisabete Ferreiro ◽  
Débora Mena ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Information Gain ◽  
Principal Component ◽  
Multidimensional Analysis ◽  
Metabolic Phenotype ◽  
Rapid Progression ◽  
Peripheral Tissues ◽  
Atp Production ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age/sex matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Pooled analysis revealed that undSOD1 patients had statistically higher glycolytic ATP production rate and lower Tfam protein content compared to controls, which were also the experimental features highlighted by multidimensional analysis. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation were found between cohorts, which may be due to age or sex. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor and, although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints that may have a diagnostic and therapeutic interest.

scholarly journals Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Barbara Commisso ◽  
Lingjun Ding ◽  
Karl Varadi ◽  
Martin Gorges ◽  
David Bayer ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Primary Motor Cortex ◽  
Structural Basis ◽  
Progressive Degeneration ◽  
New Variant ◽  
Als Patients ◽  
The Brain ◽  
Pathogenic Process ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

scholarly journals An in-depth analysis of phosphorylated tau in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid

2021 ◽  
Author(s):  
Tiziana Petrozziello ◽  
Ana C. Amaral ◽  
Simon Dujardin ◽  
Sali M.K. Farhan ◽  
James Chan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Molecular Mechanisms ◽  
Rating Scale ◽  
Phosphorylated Tau ◽  
Post Mortem ◽  
Significant Difference ◽  
Depth Analysis ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAlthough the molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are not yet fully understood, recent studies have described alterations in tau protein in both sporadic and familial ALS. However, it is unclear whether alterations in tau contribute to ALS pathogenesis. Here, we leveraged the ALS Knowledge Portal and Project MinE data sets and identified specific genetic variants clustering within the microtubule-binding domain of MAPT, which were unique to ALS cases. Furthermore, our analysis in a large post-mortem cohort of ALS and control motor cortex demonstrates that although there was no significant difference in the presence of phosphorylated tau (pTau) neuropil threads and neurofibrillary tangles between the two groups, pTau-S396 and pTau-S404 mis-localized to the nucleus and synapses in ALS. This was specific to the C-terminus phosphorylation sites as there was a significant decrease in pTau-T181 in ALS synaptoneurosomes compared to controls. Lastly, while there was no change in total tau or pTau-T181 in ALS CSF, there was a decrease in pTau-T181:tau ratio in ALS CSF, as previously reported. Importantly, CSF tau levels were increased in ALS patients diagnosed with bulbar onset ALS, while pTau-T181:tau ratio was decreased in ALS patients diagnosed with both bulbar and limb onset. Additionally, there was an inverse correlation between tau levels in the CSF and the revised ALS functional rating scale (ALSFRS-R) as well as a correlation between pTau-T181:tau ratio and ALSFRS-R. While there were no longitudinal alterations in tau, pTau-T181 and pTau-T181:tau ratio, there was an increase in the rate of ALSFRS-R decline per month associated with increases in tau levels. This decline was also inversely correlated with increases in pTau-T181 in relation to tau levels. Taken together, our findings demonstrate that, like Alzheimer’s disease, hyperphosphorylated tau is mis-localized in ALS and that decreases in CSF pTau-T181 may serve as a biomarker in ALS.

scholarly journals Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefano Garofalo ◽  
Germana Cocozza ◽  
Alessandra Porzia ◽  
Maurizio Inghilleri ◽  
Marcello Raspa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Motor Neuron ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Nkg2d Ligands ◽  
Lateral Sclerosis

AbstractIn amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis

Neurology ◽  
1997 ◽  
Vol 49 (5) ◽  
pp. 1292-1298 ◽  
Author(s):  
Ulf Ziemann ◽  
Martin Winter ◽  
Carl D. Reimers ◽  
Karin Reimers ◽  
Frithjof Tergau ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Silent Period ◽  
Intracortical Inhibition ◽  
Control Group ◽  
Cortical Silent Period ◽  
Healthy Control ◽  
Als Patients ◽  
Period Duration ◽  
Lateral Sclerosis

We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical(corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 ± 27.0% versus 45.2± 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.

scholarly journals Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

2016 ◽  
Author(s):  
Paul E Young ◽  
Stephen Kum Jew ◽  
Michael E Buckland ◽  
Roger Pamphlett ◽  
Catherine M Suter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Cytosine Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Monozygotic Twin ◽  
Sporadic Als ◽  
High Heritability ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom previous genome sequencing excluded a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of difference were largely idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all affected individuals. In both instances the differences occurred within genes and pathways related to neurobiological function and dysfunction. Our findings reveal widespread changes in epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These findings may be exploited to develop blood-based biomarkers of ALS and develop further insight into disease pathogenesis. We expect that our findings will provide a useful point of reference for further large scale studies of sporadic ALS.

scholarly journals Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

2018 ◽  
Vol 39 (7) ◽  
pp. 1283-1298 ◽  
Author(s):  
Hongxia Lei ◽  
Elisabeth Dirren ◽  
Carole Poitry-Yamate ◽  
Bernard L Schneider ◽  
Rolf Gruetter ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Disease Progression ◽  
Resonance Spectroscopy ◽  
Neurochemical Profiles ◽  
G93a Sod1 Mouse ◽  
Sod1 Mouse ◽  
G93a Sod1 ◽  
Lateral Sclerosis

In vivo 1H magnetic resonance spectroscopy (1H-MRS) investigations of amyotrophic lateral sclerosis (ALS) mouse brain may provide neurochemical profiles and alterations in association with ALS disease progression. We aimed to longitudinally follow neurochemical evolutions of striatum, brainstem and motor cortex of mice transgenic for G93A mutant human superoxide dismutase type-1 (G93A-SOD1), an ALS model. Region-specific neurochemical alterations were detected in asymptomatic G93A-SOD1 mice, particularly in lactate (−19%) and glutamate (+8%) of brainstem, along with γ-amino-butyric acid (−30%), N-acetyl-aspartate (−5%) and ascorbate (+51%) of motor cortex. With disease progression towards the end-stage, increased numbers of metabolic changes of G93A-SOD1 mice were observed (e.g. glutamine levels increased in the brainstem (>+66%) and motor cortex (>+54%)). Through ALS disease progression, an overall increase of glutamine/glutamate in G93A-SOD1 mice was observed in the striatum ( p < 0.01) and even more so in two motor neuron enriched regions, the brainstem and motor cortex ( p < 0.0001). These 1H-MRS data underscore a pattern of neurochemical alterations that are specific to brain regions and to disease stages of the G93A-SOD1 mouse model. These neurochemical changes may contribute to early diagnosis and disease monitoring in ALS patients.

Sign in / Sign up

Export Citation Format

Share Document