scholarly journals Alterations in Leptin Signaling in Amyotrophic Lateral Sclerosis (ALS)

2021 ◽  
Vol 22 (19) ◽  
pp. 10305
Author(s):  
Agueda Ferrer-Donato ◽  
Ana Contreras ◽  
Laura M. Frago ◽  
Julie A. Chowen ◽  
Carmen M. Fernandez-Martos
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disease ◽  
Leptin Receptor ◽  
Expression Profiles ◽  
Disease Onset ◽  
Plasminogen Activator Inhibitor ◽  
Inhibitory Peptide ◽  
Leptin Signaling ◽  
Activator Inhibitor Type ◽  
Lateral Sclerosis

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin’s effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin’s actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.

scholarly journals Alterations in leptin signaling in Amyotrophic Lateral Sclerosis (ALS)

2021 ◽  
Author(s):  
Agueda Ferrer-Donato ◽  
Ana Contreras ◽  
Laura M. Frago ◽  
Julie A. Chowen ◽  
Carmen M. Fernandez-Martos
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disease ◽  
Time Course ◽  
Leptin Receptor ◽  
Expression Profiles ◽  
Disease Onset ◽  
Plasminogen Activator Inhibitor ◽  
Inhibitory Peptide ◽  
Leptin Signaling ◽  
Lateral Sclerosis

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive and neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS disease and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptins effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptins actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS we assessed the mRNA and protein expression profiles of leptin, the long leptin receptor (Ob-Rb) and leptin-related signaling pathways over the time course of the disease (onset and end-stage of disease), in TDP-43A315T mice compared to age-matched WT littermates. In addition, at the selected time-points immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines (resistin and leptin) and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.

scholarly journals Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers

Brain ◽  
2014 ◽  
Vol 137 (11) ◽  
pp. 2938-2950 ◽  
Author(s):  
Axel Freischmidt ◽  
Kathrin Müller ◽  
Lisa Zondler ◽  
Patrick Weydt ◽  
Alexander E. Volk ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Expression Profiles ◽  
Consensus Sequence ◽  
Disease Onset ◽  
Therapeutic Targets ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Sequence Motif ◽  
Mutation Carriers ◽  
Disease Modifying ◽  
Lateral Sclerosis

Abstract Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

scholarly journals Mitophagy Modulation, a New Player in the Race against ALS

2021 ◽  
Vol 22 (2) ◽  
pp. 740
Author(s):  
Enrique Madruga ◽  
Inés Maestro ◽  
Ana Martínez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Unknown Etiology ◽  
Drug Candidates ◽  
Relevant Evidence ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals In Vivo Validation of Bimolecular Fluorescence Complementation (BiFC) to Investigate Aggregate Formation in Amyotrophic Lateral Sclerosis (ALS)

2020 ◽  
Author(s):  
Emily K Don ◽  
Alina Maschirow ◽  
Rowan A W Radford ◽  
Natalie M Scherer ◽  
Andres Vidal-Itriago ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Onset ◽  
Bimolecular Fluorescence Complementation ◽  
Aggregate Formation ◽  
Reporter Protein ◽  
Fluorescent Reporter ◽  
Lateral Sclerosis ◽  
Fluorescence Complementation ◽  
Bimolecular Fluorescence

AbstractAmyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that is characterized by the progressive loss of motor neurons within the spinal cord, brainstem and motor cortex. Although ALS clinically manifests as a heterogeneous disease, with varying disease onset and survival, a unifying feature is the presence of ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, the precise mechanisms linking protein inclusions and aggregation to neuronal loss are currently poorly understood.Bimolecular Fluorescence Complementation (BiFC) takes advantage the association of fluorophore fragments (non-fluorescent on their own) that are attached to an aggregation prone protein of interest. Interaction of the proteins of interest allows for the fluorescent reporter protein to fold into its native state and emit a fluorescent signal. Here, we combined the power of BiFC with the advantages of the zebrafish system to validate, optimize and visualize of the formation of ALS-linked aggregates in real time in a vertebrate model. We further provide in vivo validation of the selectivity of this technique and demonstrate reduced spontaneous self-assembly of the non-fluorescent fragments in vivo by introducing a fluorophore mutation. Additionally, we report preliminary findings on the dynamic aggregation of the ALS-linked hallmark proteins Fus and TDP-43 in their corresponding nuclear and cytoplasmic compartments using BiFC.Overall, our data demonstrates the suitability of this BiFC approach to study and characterize ALS-linked aggregate formation in vivo. Importantly, the same principle can be applied in the context of other neurodegenerative diseases and has therefore critical implications to advance our understanding of pathologies that underlie aberrant protein aggregation.

scholarly journals Consumption of unregulated food items (false morels) and risk for neurodegenerative disease (amyotrophic lateral sclerosis)

2020 ◽  
pp. 94-99
Author(s):  
P.S. Spencer ◽  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Free Radicals ◽  
Environmental Factors ◽  
Neurodegenerative Disease ◽  
Strong Evidence ◽  
Western Europe ◽  
World War ◽  
Food Items ◽  
Sporadic Als ◽  
Lateral Sclerosis

Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.

Discordant performance on the ‘Reading the Mind in the Eyes’ Test, based on disease onset in amyotrophic lateral sclerosis

2016 ◽  
Vol 17 (7-8) ◽  
pp. 467-472 ◽  
Author(s):  
Tom Burke ◽  
Marwa Elamin ◽  
Peter Bede ◽  
Marta Pinto-Grau ◽  
Katie Lonergan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Onset ◽  
The Mind ◽  
Lateral Sclerosis

Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model

2007 ◽  
Vol 204 (1) ◽  
pp. 260-263 ◽  
Author(s):  
Jonathan F. Grunfeld ◽  
Yael Barhum ◽  
Netta Blondheim ◽  
Jose-Martin Rabey ◽  
Eldad Melamed ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Onset ◽  
Lateral Sclerosis

scholarly journals Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

2015 ◽  
Vol 77 (3-4) ◽  
Author(s):  
B. Chandrasoma ◽  
D. Balfe ◽  
T. Naik ◽  
A. Elsayegh ◽  
M. Lewis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pulmonary Function ◽  
Muscle Weakness ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Disease Onset ◽  
Group Versus ◽  
Combination Methods ◽  
Lateral Sclerosis

Background. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of Amyotrophic Lateral Sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. Methods. Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. Results. There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced(43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p=0.15) and the RV to be higher (157.4% versus 135.9%, P=0.24). Conclusions. ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities.

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