The multifaceted role of kinases in amyotrophic lateral sclerosis: genetic, pathological and therapeutic implications

Abstract Amyotrophic lateral sclerosis is the most common degenerative disorder of motor neurons in adults. As there is no cure, thousands of individuals who are alive at present will succumb to the disease. In recent years, numerous causative genes and risk factors for amyotrophic lateral sclerosis have been identified. Several of the recently identified genes encode kinases. In addition, the hypothesis that (de)phosphorylation processes drive the disease process resulting in selective motor neuron degeneration in different disease variants has been postulated. We re-evaluate the evidence for this hypothesis based on recent findings and discuss the multiple roles of kinases in amyotrophic lateral sclerosis pathogenesis. We propose that kinases could represent promising therapeutic targets. Mainly due to the comprehensive regulation of kinases, however, a better understanding of the disturbances in the kinome network in amyotrophic lateral sclerosis is needed to properly target specific kinases in the clinic.

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Diabetes Mellitus and Amyotrophic Lateral Sclerosis: A Systematic Review

Biomolecules ◽

10.3390/biom11060867 ◽

2021 ◽

Vol 11 (6) ◽

pp. 867

Author(s):

Laura Ferri ◽

Paola Ajdinaj ◽

Marianna Gabriella Rispoli ◽

Claudia Carrarini ◽

Filomena Barbone ◽

...

Keyword(s):

Diabetes Mellitus ◽

Amyotrophic Lateral Sclerosis ◽

Glucose Metabolism ◽

Motor Neurons ◽

Protective Role ◽

Clear Correlation ◽

Metabolic System ◽

Degenerative Disorder ◽

Lateral Sclerosis

Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS. Methods: We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered. Results: DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects. Conclusions: The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.

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Nutrient Effects on Motor Neurons and the Risk of Amyotrophic Lateral Sclerosis

Nutrients ◽

10.3390/nu13113804 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3804

Author(s):

Polina S. Goncharova ◽

Tatiana K. Davydova ◽

Tatiana E. Popova ◽

Maxim A. Novitsky ◽

Marina M. Petrova ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Randomized Clinical Trials ◽

Progression Rate ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Vitamin B9 ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression. Methods: We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010–2020. Discussion: We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development. Conclusion: The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.

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Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis

Journal of Alzheimer s Disease ◽

10.3233/jad-201472 ◽

2021 ◽

pp. 1-15

Author(s):

Vasily Vorobyov ◽

Alexander Deev ◽

Frank Sengpiel ◽

Vladimir Nebogatikov ◽

Aleksey A. Ustyugov

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Neurons ◽

Primary Motor Cortex ◽

Beta Activity ◽

Systemic Injection ◽

Eeg Spectra ◽

Electroencephalogram Eeg ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

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Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow

Nature Communications ◽

10.1038/s41467-020-19177-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Vartika Mishra ◽

Diane B. Re ◽

Virginia Le Verche ◽

Mariano J. Alvarez ◽

Alessandro Vasciaveo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Death Receptor ◽

Cell Interaction ◽

Type Motor ◽

Cellular Compartments ◽

Death Receptor 6 ◽

Lateral Sclerosis

Abstract Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ligand-mediated interactions between distinct cellular compartments. To test this approach, we selected a model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs) by an unknown mechanism. Our integrative analysis that combines proteomics and regulatory network analysis infers the interaction between astrocyte-released amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. Our results support the usefulness of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS and posit that the proposed methodology is not restricted to this biological context and could be used in a variety of other non-cell-autonomous communication mechanisms.

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Role of PET and SPECT in the Study of Amyotrophic Lateral Sclerosis

BioMed Research International ◽

10.1155/2014/237437 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 14

Author(s):

Angelina Cistaro ◽

Vincenzo Cuccurullo ◽

Natale Quartuccio ◽

Marco Pagani ◽

Maria Consuelo Valentini ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Primary Motor Cortex ◽

Clinical Laboratory ◽

Resonance Imaging ◽

Muscle Paralysis ◽

Additional Information ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis has been defined as a “heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord.” A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals.

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Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

Neurology Genetics ◽

10.1212/nxg.0000000000000394 ◽

2020 ◽

Vol 6 (1) ◽

pp. e394

Author(s):

Julia L. Keith ◽

Emily Swinkin ◽

Andrew Gao ◽

Samira Alminawi ◽

Ming Zhang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Mutation Carrier ◽

Double Immunofluorescence ◽

Motor Neuron Degeneration ◽

Respiratory Involvement ◽

Sporadic Als ◽

Immunofluorescence Labeling ◽

Normal Controls ◽

Lateral Sclerosis

ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

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Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5021694 ◽

2020 ◽

Vol 2020 ◽

pp. 1-29

Author(s):

Teresa Cunha-Oliveira ◽

Liliana Montezinho ◽

Catarina Mendes ◽

Omidreza Firuzi ◽

Luciano Saso ◽

...

Keyword(s):

Oxidative Stress ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Therapeutic Benefit ◽

Pharmacological Intervention ◽

Antioxidant Compounds ◽

Pathological Feature ◽

Beneficial Effects ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

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Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis

Brain Sciences ◽

10.3390/brainsci10100675 ◽

2020 ◽

Vol 10 (10) ◽

pp. 675

Author(s):

Hyun-Jun Choi ◽

Sun Joo Cha ◽

Jang-Won Lee ◽

Hyung-Jun Kim ◽

Kiyoung Kim

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Protein Kinase ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Critical Role ◽

Glycogen Synthase Kinase 3 ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

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Existing and Emerging Metabolomic Tools for ALS Research

Genes ◽

10.3390/genes10121011 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1011 ◽

Cited By ~ 4

Author(s):

Christine Germeys ◽

Tijs Vandoorne ◽

Valérie Bercier ◽

Ludo Van Den Bosch

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Energy Metabolism ◽

Motor Neurons ◽

Therapeutic Strategies ◽

Metabolic State ◽

Advanced Technologies ◽

Novel Therapeutic Strategies ◽

Lateral Sclerosis ◽

Novel Therapeutic

Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies.

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Progress in Clinical Neurosciences: The Evidence for ALS as a Multisystems Disorder of Limited Phenotypic Expression

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100001505 ◽

2001 ◽

Vol 28 (4) ◽

pp. 283-298 ◽

Cited By ~ 48

Author(s):

Michael J. Strong

Keyword(s):

Motor Neurons ◽

Phenotypic Variability ◽

Phenotypic Expression ◽

Disease Process ◽

Cellular Level ◽

Central Component ◽

Biological Processes ◽

Motor Neuron Degeneration ◽

Biological Heterogeneity ◽

Lateral Sclerosis

Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.

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