Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3–5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.

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Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.784833 ◽

2021 ◽

Vol 15 ◽

Author(s):

Iris-Stefania Pasniceanu ◽

Manpreet Singh Atwal ◽

Cleide Dos Santos Souza ◽

Laura Ferraiuolo ◽

Matthew R. Livesey

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Repeat Expansion ◽

Neuronal Function ◽

Repeat Expansion Mutation ◽

Expansion Mutation ◽

The Impact ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

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A streamlined CRISPR workflow to introduce mutations and generate isogenic iPSCs for modeling amyotrophic lateral sclerosis

10.1101/2021.06.21.449257 ◽

2021 ◽

Author(s):

Eric Deneault ◽

Mathilde Chaineau ◽

Maria Jose Castellanos-Montiel ◽

Anna Kristyna Franco Flores ◽

Ghazal Haghi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Control Line ◽

Human Neurons ◽

Recent Developments ◽

Induced Pluripotent ◽

Specific Contribution ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) represents a complex neurodegenerative disorder with significant genetic heterogeneity. To date, both the genetic etiology and the underlying molecular mechanisms driving this disease remain poorly understood, although in recent years a number of studies have highlighted a number of genetic mutations causative for ALS. With these mutations pointing to potential pathways that may be affected within individuals with ALS, having the ability to generate human neurons and other disease relevant cells containing these mutations becomes even more critical if new therapies are to emerge. Recent developments with the advent of induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing fields gave us the tools to introduce or correct a specific mutation at any site within the genome of an iPSC, and thus model the specific contribution of risk mutations. In this study we describe a rapid and efficient way to either introduce a mutation into a control line, or to correct a mutation, generating an isogenic control line from patient-derived iPSCs with a given mutation. The mutations introduced were the G93A mutation into SOD1 or H517Q into FUS, and the mutation corrected was a patient iPSC line with I114T in SOD1. A combination of small molecules and growth factors were used to guide a stepwise differentiation of the edited cells into motor neurons in order to demonstrate that disease-relevant cells could be generated for downstream applications. Through a combination of iPSCs and CRISPR editing, the cells generated here will provide fundamental insights into the molecular mechanisms underlying neuron degeneration in ALS.

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

Journal of Personalized Medicine ◽

10.3390/jpm11070671 ◽

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.

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Frontotemporal dementia and amyotrophic lateral sclerosis: Revisiting one of the first case reports with neuropathological examination

Dementia & Neuropsychologia ◽

10.1590/s1980-57642014dn81000013 ◽

2014 ◽

Vol 8 (1) ◽

pp. 83-86 ◽

Cited By ~ 2

Author(s):

Ricardo Nitrini

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Motor Neurons ◽

Case Reports ◽

Rare Event ◽

Motor Impairments ◽

Late 20Th Century ◽

First Case ◽

Lateral Sclerosis ◽

Neuropathological Examination

ABSTRACT The occurrence of dementia in amyotrophic lateral sclerosis (ALS) was only widely recognized in the late 20th century. Hitherto, it was believed that dementia was a rare event due to the fortuitous association with other diseases. In 1924, Kostantin Nikolaevich Tretiakoff and Moacyr de Freitas Amorim reported a case of dementia with features of frontotemporal dementia (FTD) that preceded the motor signs of ALS. Neuropathological examination confirmed ALS and found no signs of other dementia-causing diseases. The authors hypothesized that dementia was part of ALS and recommended the search for signs of involvement of motor neurons in cases of dementia with an ill-defined clinical picture, a practice currently accepted in the investigation of cases of FTD. This was one of the first descriptions of dementia preceding the motor impairments of ALS and was published in Portuguese and French in Memórias do Hospício de Juquery.

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Spatiotemporal Dynamics of Molecular Pathology in Amyotrophic Lateral Sclerosis

10.1101/389270 ◽

2018 ◽

Cited By ~ 2

Author(s):

Silas Maniatis ◽

Tarmo Äijö ◽

Sanja Vickovic ◽

Catherine Braine ◽

Kristy Kang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Early Time ◽

Spatiotemporal Dynamics ◽

Course Of Disease ◽

Molecular Events ◽

Als Patients ◽

Lateral Sclerosis

AbstractParalysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify novel pathway dynamics, regional differences between microglia and astrocyte populations at early time-points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.One Sentence SummaryAnalysis of the ALS spinal cord using Spatial Transcriptomics reveals spatiotemporal dynamics of disease driven gene regulation.

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Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2012.146 ◽

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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Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Science ◽

10.1126/science.aav9776 ◽

2019 ◽

Vol 364 (6435) ◽

pp. 89-93 ◽

Cited By ~ 74

Author(s):

Silas Maniatis ◽

Tarmo Äijö ◽

Sanja Vickovic ◽

Catherine Braine ◽

Kristy Kang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Early Time ◽

Course Of Disease ◽

Molecular Events ◽

Motor Neuron Loss ◽

Als Patients ◽

Lateral Sclerosis

Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.

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Sympathetic Hyperactivity and Sympathovagal Imbalance in Amyotrophic Lateral Sclerosis

European Neurological Review ◽

10.17925/enr.2013.08.01.46 ◽

2012 ◽

Vol 8 (1) ◽

pp. 46 ◽

Cited By ~ 12

Author(s):

Toshio Shimizu ◽

Keyword(s):

Heart Rate ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Hypertensive Crisis ◽

Individual Treatment ◽

Sympathetic Hyperactivity ◽

Sympathovagal Imbalance ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with progressive loss of upper and lower motor neurons. Autonomic nervous abnormalities, including sympathetic hyperactivity and sympathovagal imbalance, have been found in both early and advanced stages of ALS. In early stage, the dysfunction may be subclinical. Occasionally, elevated blood pressure or heart rate and increased sweating may be observed. In advanced stage when ventilators are required, the sympathetic hyperactivity may lead to hypertensive crisis without counter-regulation of heart rate, followed by the consecutive circulatory collapse, known as the ‘autonomic storm’. The symptoms of ‘autonomic storm’ are similar to that of ‘baroreflex failure’, and ‘autonomic storm’ indicates poor prognosis and may result in sudden death. Careful evaluation and individual treatment are strongly suggested, although appropriate therapeutic approaches have not been established. Causative central nervous lesions remain to be elucidated, although the limbic system may be involved. The autonomic dysfunction further supports the concept that ALS is a multisystem-degenerative disease.

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Clonally expanded CD8 T cells characterize Amyotrophic Lateral Sclerosis 4

10.21203/rs.3.rs-798338/v1 ◽

2021 ◽

Author(s):

Ivan Marazzi ◽

Laura Campisi ◽

Shahab Chizari ◽

Anastasia Gromova ◽

Frederick Arnold ◽

...

Keyword(s):

T Cells ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cd8 T Cells ◽

Neurodegenerative Disorder ◽

T Cell Response ◽

Immune Functions ◽

Potential Biomarker ◽

Motor Difficulties ◽

Lateral Sclerosis

Abstract Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder that affects motor neurons in the brain and spinal cord, causing progressive loss of voluntary muscle control1,2. ALS heterogeneity includes the age of manifestation, the rate of progression, and the anatomical sites of symptom onset. In addition, disease-causing mutations in specific genes have been identified and are used to catalog different subtypes of ALS3. Interestingly, several ALS-associated genes have been shown to affect immune functions, and a variety of aberrant inflammatory events have been reported in patients and mouse models4-11, suggesting that specific immune features can also account for ALS heterogeneity. ALS4 is characterized by juvenile-onset and slow progression12. After experiencing mild symptoms during their childhood, ALS4 patients show motor difficulties by their 30s, and most of them require walkers or wheelchairs by their 50s. ALS4 is caused by dominant mutations in the gene SETX. Using Setx knock-in (KI) mice carrying the ALS4 causative L389S mutation, we discovered an immunological signature consisting of clonally activated CD8 T cells specifically in the central nervous system and blood of KI animals. Expansion of antigen-specific CD8 T cells mirrors disease progression. Bone marrow transplantation experiments indicate an essential role of the immune system in ALS4 neurodegeneration. Furthermore, we found that clonally expanded CD8 T cells circulate in the peripheral blood of ALS4 patients. Our results provide evidence of an antigen-specific CD8 T cell response linked to ALS4, and can serve not only to unravel specific disease mechanisms, but as a potential biomarker of disease activity.

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Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Antioxidants ◽

10.3390/antiox10081328 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1328

Author(s):

Valentina Novak ◽

Boris Rogelj ◽

Vera Župunski

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Therapeutic Potential ◽

Treatment Options ◽

Common Disease ◽

Beneficial Effects ◽

Disease Spectrum ◽

New Compounds ◽

And Oxidative Stress ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.

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