scholarly journals Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yannick von Grabowiecki ◽  
Paula Abreu ◽  
Orphee Blanchard ◽  
Lavinia Palamiuc ◽  
Samir Benosman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscle Atrophy ◽  
Ubiquitin Ligase ◽  
Target Genes ◽  
Muscular Atrophy ◽  
Common Denominator ◽  
P53 Family ◽  
Protein Levels ◽  
Als Patients ◽  
Lateral Sclerosis

Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.

scholarly journals Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 906
Author(s):  
Nimeshan Geevasinga ◽  
Mehdi Van den Bos ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Excitability ◽  
Muscular Atrophy ◽  
Close Relationship ◽  
Bulbar Onset ◽  
Als Patients ◽  
Transcranial Magnetic Simulation ◽  
Cortical Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

scholarly journals Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

2021 ◽  
Vol 8 (1) ◽  
pp. 25-38
Author(s):  
Marisa Cappella ◽  
Pierre-François Pradat ◽  
Giorgia Querin ◽  
Maria Grazia Biferi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Monogenic Disease ◽  
Sporadic Als ◽  
Pathological Mechanism ◽  
Huge Impact ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

scholarly journals Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya

2020 ◽  
Author(s):  
Elin Roos ◽  
Sebastian K.T.S. Wärmländer ◽  
Jeremy Meyer ◽  
Sabrina B. Sholts ◽  
Jüri Jarvet ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Systemic Exposure ◽  
Medical Procedure ◽  
Manganese Neurotoxicity ◽  
Causative Relationship ◽  
Genetic And Environmental Factors ◽  
Exposure Routes ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.

scholarly journals Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

2015 ◽  
Vol 112 (26) ◽  
pp. 8100-8105 ◽  
Author(s):  
James C. Dodge ◽  
Christopher M. Treleaven ◽  
Joshua Pacheco ◽  
Samantha Cooper ◽  
Channa Bao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Targets ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Sensory Neuropathy ◽  
Disease Course ◽  
Hereditary Sensory Neuropathy ◽  
Als Patients ◽  
Lateral Sclerosis

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.

scholarly journals Role of the nigrosome 1 absence as a biomarker in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
María Isabel Moreno-Gambín ◽  
José I. Tembl ◽  
Miguel Mazón ◽  
Antonio José Cañada-Martínez ◽  
Luis Martí-Bonmatí ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Substantia Nigra ◽  
Muscular Atrophy ◽  
Brain Mri ◽  
Transcranial Sonography ◽  
Male Sex ◽  
Als Patients ◽  
Independent Marker ◽  
Lateral Sclerosis

Abstract Introduction The absence of nigrosome 1 on brain MRI and the hyperechogenicity of substantia nigra (SNh) by transcranial sonography are two useful biomarkers in the diagnosis of parkinsonisms. We aimed to evaluate the absence of nigrosome 1 in amyotrophic lateral sclerosis (ALS) and to address its meaning. Methods 136 ALS patients were recruited, including 16 progressive muscular atrophy (PMA) and 22 primary lateral sclerosis (PLS) patients. The SNh area was measured planimetrically by standard protocols. The nigrosome 1 status was qualitatively assessed by two blind evaluators in susceptibility weight images of 3T MRI. Demographic and clinical data were collected and the C9ORF72 expansion was tested in all patients. Results Nigrosome 1 was absent in 30% of ALS patients (36% of PLS, 29% of classical ALS and 19% of PMA patients). There was no relationship between radiological and clinical laterality, nor between nigrosome 1 and SNh area. Male sex (OR = 3.63 [1.51, 9.38], p = 0.005) and a higher upper motor neuron (UMN) score (OR = 1.10 [1.02, 1.2], p = 0.022) were independently associated to nigrosome 1 absence, which also was an independent marker of poor survival (HR = 1.79 [1.3, 2.8], p = 0.013). Conclusion In ALS patients, the absence of nigrosome 1 is associated with male sex, UMN impairment and shorter survival. This suggests that constitutional factors and the degree of pyramidal involvement are related to the substantia nigra involvement in ALS. Thus, nigrosome 1 could be a marker of a multisystem degeneration, which in turn associates to poor prognosis.

scholarly journals Cognitive Performance of Patients with Adult 5q-Spinal Muscular Atrophy and with Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Alma Osmanovic ◽  
Gary Wieselmann ◽  
Lucas Mix ◽  
Hannah Alexandra Siegler ◽  
Mareike Kumpe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cognitive Function ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Vocabulary Test ◽  
Cross Sectional ◽  
Physical Handicap ◽  
Als Patients ◽  
Lateral Sclerosis

Motor neuron diseases, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), share several clinical similarities while differing substantially in etiology, disease onset and progression. Cognitive dysfunction, a clinically relevant non-motor feature in a substantial proportion of ALS patients, has been less frequently investigated in SMA. In this prospective multicenter cross-sectional study, cognitive function was assessed by the Edinburgh Cognitive (and Behavioural) ALS Screen (ECAS) and a German vocabulary test (Wortschatztest, WST) in 34 adult patients with SMA types 2–4 and in 34 patients with ALS. Demographic and clinical parameters were assessed to identify factors that potentially influence cognitive function. While SMA and ALS patients were comparable in the vocabulary test, on average, SMA patients performed better than ALS patients in the cognitive domains of memory, language and executive function. Better cognitive abilities in SMA patients seemed to be related to the early onset, rather than the extent or the duration, of their physical handicap. Future studies should focus on disease-specific cognitive functions in SMA.

scholarly journals Dissociated leg muscle atrophy in amyotrophic lateral sclerosis/motor neuron disease: the ‘split-leg’ sign

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Young Gi Min ◽  
Seok-Jin Choi ◽  
Yoon-Ho Hong ◽  
Sung-Min Kim ◽  
Je-Young Shin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Muscle Atrophy ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Healthy Controls ◽  
Abductor Hallucis ◽  
Lateral Sclerosis

Abstract Disproportionate muscle atrophy is a distinct phenomenon in amyotrophic lateral sclerosis (ALS); however, preferentially affected leg muscles remain unknown. We aimed to identify this split-leg phenomenon in ALS and determine its pathophysiology. Patients with ALS (n = 143), progressive muscular atrophy (PMA, n = 36), and age-matched healthy controls (HC, n = 53) were retrospectively identified from our motor neuron disease registry. We analyzed their disease duration, onset region, ALS Functional Rating Scale-Revised Scores, and results of neurological examination. Compound muscle action potential (CMAP) of the extensor digitorum brevis (EDB), abductor hallucis (AH), and tibialis anterior (TA) were reviewed. Defined by CMAPEDB/CMAPAH (SIEDB) and CMAPTA/CMAPAH (SITA), respectively, the values of split-leg indices (SI) were compared between these groups. SIEDB was significantly reduced in ALS (p < 0.0001) and PMA (p < 0.0001) compared to the healthy controls (HCs). SITA reduction was more prominent in PMA (p < 0.05 vs. ALS, p < 0.01 vs. HC), but was not significant in ALS compared to the HCs. SI was found to be significantly decreased with clinical lower motor neuron signs (SIEDB), while was rather increased with clinical upper motor neuron signs (SITA). Compared to the AH, TA and EDB are more severely affected in ALS and PMA patients. Our findings help to elucidate the pathophysiology of split-leg phenomenon.

scholarly journals Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 84
Author(s):  
Alma Osmanovic ◽  
Isabel Gogol ◽  
Helge Martens ◽  
Maylin Widjaja ◽  
Kathrin Müller ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorder ◽  
Muscular Atrophy ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Sporadic Cases ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.

scholarly journals A single case study: myoelectrically controlled exoskeletal mobilizer for amyotrophic lateral sclerosis (ALS) patients

1989 ◽  
Vol 13 (3) ◽  
pp. 145-148 ◽  
Author(s):  
W. F. Sauter ◽  
G. Bush ◽  
J. Sommerville
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Single Case ◽  
Clinical Pathology ◽  
Single Case Study ◽  
Progressive Muscle Weakness ◽  
Als Patients ◽  
Lateral Sclerosis

Introduction and clinical pathology of Amyotrophic Lateral Sclerosis (ALS) Amyotrophic Lateral Sclerosis (ALS) also known as Lou Gehrig's disease is the generic name for progressive muscular atrophy and bulbar palsy. It refers to all disorders of the cortico spinal pathways which are characterized by progressive muscle weakness. After multiple sclerosis, ALS is the most common purely neurological disorder (Janiszewski et al. 1983). Information available from the ALS Society indicates that the most common age of onset is 55 years.

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