-
1.
Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?
Scaricamazza, S, Salvatori, I, Ferri, A, Valle, C
Cells. 2021;(3)
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.
-
2.
New technologies and Amyotrophic Lateral Sclerosis - Which step forward rushed by the COVID-19 pandemic?
Pinto, S, Quintarelli, S, Silani, V
Journal of the neurological sciences. 2020;:117081
-
-
Free full text
-
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fast-progressive neurodegenerative disease leading to progressive physical immobility with usually normal or mild cognitive and/or behavioural involvement. Many patients are relatively young, instructed, sensitive to new technologies, and professionally active when developing the first symptoms. Older patients usually require more time, encouragement, reinforcement and a closer support but, nevertheless, selecting user-friendly devices, provided earlier in the course of the disease, and engaging motivated carers may overcome many technological barriers. ALS may be considered a model for neurodegenerative diseases to further develop and test new technologies. From multidisciplinary teleconsults to telemonitoring of the respiratory function, telemedicine has the potentiality to embrace other fields, including nutrition, physical mobility, and the interaction with the environment. Brain-computer interfaces and eye tracking expanded the field of augmentative and alternative communication in ALS but their potentialities go beyond communication, to cognition and robotics. Virtual reality and different forms of artificial intelligence present further interesting possibilities that deserve to be investigated. COVID-19 pandemic is an unprecedented opportunity to speed up the development and implementation of new technologies in clinical practice, improving the daily living of both ALS patients and carers. The present work reviews the current technologies for ALS patients already in place or being under evaluation with published publications, prompted by the COVID-19 pandemic.
-
3.
Denouement of Chemicals on Amyotrophic Lateral Sclerosis: Is Green Chemistry the Answer.
Fayaz, F, Pottoo, FH, Shafi, S, Wani, MA, Wakode, S, Sharma, A
Medicinal chemistry (Shariqah (United Arab Emirates)). 2020;(8):1058-1068
Abstract
Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as "Lou Gehrig's disease", a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.
-
4.
Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis.
Blasco, H, Lanznaster, D, Veyrat-Durebex, C, Hergesheimer, R, Vourch, P, Maillot, F, Andres, CR, Pradat, PF, Corcia, P
Expert review of neurotherapeutics. 2020;(9):907-919
Abstract
INTRODUCTION Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment. AREA COVERED Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics. EXPERT OPINION The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.
-
5.
The Role of Iron in Amyotrophic Lateral Sclerosis.
Bu, XL, Xiang, Y, Guo, Y
Advances in experimental medicine and biology. 2019;:145-152
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The etiology and pathogenesis of this devastating disease remain largely unknown. Increasing evidence suggests that iron accumulation is involved in the onset and progression of ALS. In this review, we discuss the regulation of iron homoeostasis in the brain, the misregulation of iron homeostasis in ALS, and its possible roles in the mechanism of the disease. Finally, we summarize the recent progress and problems with respect to iron chelator therapies on ALS, aiming to propose a new therapeutic strategy to ameliorate the progression of the disease.
-
6.
[A Brief Review on Recent Epidemiologic Literature and Risk Factors of Amyotrophic Lateral Sclerosis].
Narita, Y
Brain and nerve = Shinkei kenkyu no shinpo. 2019;(11):1129-1137
Abstract
This brief review of recent epidemiologic literature and risk factors of sporadic ALS found that the incidence and prevalence of the condition is higher among Caucasians and lower in East Asians, with the Japanese in the middle. The review also found that worldwide, the prevalence increases with age and the condition is 1.3 to 1.6 times higher in males than in females. The number of patients with ALS was calculated based on official diagnostic certificates from fiscal 1997 to 2015 obtained from a registry managed by Japan's Ministry of Health, Labor and Welfare. The data matched with those reported in the guidelines of the Japanese Society of Neurology (2013), with an incidence of 1.1-2.5, and prevalence 7.0-8.5/100,000 people. Smoking has been considered an established risk factor for sporadic ALS. The following possible risk factors have been speculated but are to be confirmed: excessive physical activity, head trauma, farming, environmental pollutants, pesticides, exposure to certain metals/heavy metals, electromagnetic fields, alcohol, low BMI, and low-density lipoprotein. Bandres-Ciga et al. applied linkage disequilibrium score regression and Mendelian randomization to a large data set and concluded that elevated low-density lipoprotein cholesterol is a causal risk factor for ALS.
-
7.
CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS).
Kruminis-Kaszkiel, E, Juranek, J, Maksymowicz, W, Wojtkiewicz, J
International journal of molecular sciences. 2018;(3)
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs) at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS) pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin.
-
8.
The increasing importance of environmental conditions in amyotrophic lateral sclerosis.
Riancho, J, Bosque-Varela, P, Perez-Pereda, S, Povedano, M, de Munaín, AL, Santurtun, A
International journal of biometeorology. 2018;(8):1361-1374
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients.
-
9.
Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Freischmidt, A, Müller, K, Ludolph, AC, Weishaupt, JH, Andersen, PM
JAMA neurology. 2017;(1):110-113
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.
-
10.
Manganese in manganism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease: A narrative review.
Proudfoot, O
Neurology India. 2017;(6):1241-1247
-
-
Free full text
-
Abstract
The collective evidence to date suggests that environmental exposure to excessive amounts of manganese (Mn) can cause a neurodegenerative condition known as manganism. It is now also relatively clear that Mn is involved in the pathogenesis of Alzheimer's disease and at least some prion diseases. The potential involvement of Mn in a panel of other neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease has been suggested and investigated, but the results to date are somewhat inconclusive. Herein, previously reported experimental studies investigating the involvement of Mn in the pathogenesis of these conditions are narratively reviewed.