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Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 November 2024) | Viewed by 25139

Special Issue Editor


E-Mail Website
Guest Editor
University Hospital Bern, Bern, Switzerland
Interests: translational preclinical models of neurodegenerative diseases; disease mechanisms; adaptive mechanisms; endoplasmic reticulum stress; mitochondria; E- mitochondria membranes; selective autophagy in aging and ALS; mitophagy; axon trafficking deficits; heat shock proteins; human iPSC-derived neurons; iPSC-derived brain organoids; extracellular vesicles; transcriptomics; proteomics; spatial proteomics; motor neuron subtype vulnerability; spinal and cerebellar circuits and their modulation; synaptic dysfunction; growth factors and neuroprotection; ASOs; gene therapy; compounds for therapy

Special Issue Information

Dear Colleagues,

It is well-known that amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, typically exemplified by the degeneration of both upper and lower motor neurons, leading to muscle atrophy, paralysis, and eventual death of the patient due to respiratory failure. With the advancement in technology, the search for ALS-linked genes has been conducted through genome-wide association studies and “next-generation” sequencing techniques, which have led to the identification of several new ALS-linked genes. Of the 50 potentially causative or disease-modifying genes identified thus far, pathogenic variants of SOD1, C9ORF72, FUS, and TARDBP occur most frequently in familial ALS. Mechanistically, several studies have shown that disruptions in axonal trafficking, ER proteostasis and crosstalk with mitochondria, and impairments in autophagy can result in motor neuron degeneration. Motor neurons are highly susceptible to perturbations in these pathways, and abnormal endoplasmic reticulum (ER) and mitochondrial stress both trigger the unfolded protein response (UPR). Moreover, a potential disruption of Ca2+handling by the ER/mitochondria causes the generation of reactive oxygen species and thus induces cellular stress. Several lines of evidence indicate that disruption in Ca2+ homeostasis and the subsequent alteration in neuronal excitability are common phenomena reported in ALS patients. Notably, impaired glutamate neurotransmission and, consequently, glutamate-triggered Ca2+entry, together with reduced glial glutamate uptake, are associated with motor neuron degeneration. Strategies aiming to modulate either ER stress or the mitochondrial response are crucial. Similarly, approaches involving the modulation of neuronal excitability in a cell-type- and disease-stage-dependent manner are critical for the development of future therapies. This Special Issue offers an open access forum that aims to bring together a collection of original research as well as review articles providing a broad perspective on ALS genetics, disease mechanisms, and therapeutic strategies for targeting the pathology. We hope to provide a research-stimulating resource for the important subject of ALS genetics and pathomechanisms. Suggested topics of interest include the following: hormesis; ER stress and mitochondrial crosstalk in ALS; cell clearance machinery; the modulation of spinal and cortical networks; and exosomes, epigenetics, and new model systems that can be employed to model and characterize novel ALS mechanisms.

Prof. Dr. Smita Saxena
Guest Editor

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Keywords

  • genetics of ALS/FTD
  • ER stress and UPR
  • mitochondria and mitochondrial-associated membranes
  • Ca2+ signaling
  • excitotoxicity/neuronal networks
  • synaptic dysfunction
  • therapeutic strategies

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Published Papers (9 papers)

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Review

27 pages, 831 KiB  
Review
Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis
by Kathryn R. Moss and Smita Saxena
Cells 2025, 14(1), 47; https://doi.org/10.3390/cells14010047 - 3 Jan 2025
Viewed by 1328
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and impaired synaptic function. While Schwann cells have been traditionally viewed as peripheral supportive cells, especially in motor neuron disease, recent evidence indicates that they play a significant role in ALS by impacting motor neuron survival and plasticity, influencing inflammatory responses, and altering myelination processes. Furthermore, advancements in understanding Schwann cell pathology in ALS combined with lessons learned from studying Charcot–Marie–Tooth disease Type 1 (CMT1) suggest potential therapeutic strategies targeting these cells may support nerve repair and slow disease progression. Overall, this review aims to provide comprehensive insights into Schwann cell classification, physiology, and function, underscoring the critical pathological contributions of Schwann cells in ALS and suggests new avenues for targeted therapeutic interventions aimed at modulating Schwann cell function in ALS. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>Multiple types of Schwann cells in the peripheral nervous system. The location and morphology of Schwann cells, including myelinating Schwann cells, Remak Schwann cells (adapted with permission from Ref. [<a href="#B10-cells-14-00047" class="html-bibr">10</a>] 2005, Elsevier Inc.), perisynaptic Schwann cells, and satellite glia (adapted with permission from Ref. [<a href="#B17-cells-14-00047" class="html-bibr">17</a>]) are depicted.</p>
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15 pages, 1195 KiB  
Review
Potential Therapeutic Interventions Targeting NAD+ Metabolism for ALS
by Samuel Lundt and Shinghua Ding
Cells 2024, 13(17), 1509; https://doi.org/10.3390/cells13171509 - 9 Sep 2024
Cited by 1 | Viewed by 2721
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD+ can be synthesized from three different intracellular pathways, but it is the NAD+ salvage pathway that generates the largest proportion of NAD+. Impaired NAD+ homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD+ homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD+ metabolism, either by administering NAD+ precursor metabolites or small molecules that alter NAD+-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD+ metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>NAD<sup>+</sup> salvage pathway and NAD<sup>+</sup>-dependent enzymatic reactions. NAD<sup>+</sup> salvage pathway (<b>top</b>) NAM or NR are converted to NMN by NAMPT or NMRK, respectively. NMNAT generates NAD<sup>+</sup> from NMN. NAD<sup>+</sup> can be reversibly reduced and oxidized or utilized by NADases (SIRTs, PARPs, CD38, and SARM1), which produce NAM as a byproduct that can be re-used to form NAD<sup>+</sup>. NADase reactions (<b>bottom</b>). PARPs add ADPR to substrates. SIRTs remove acetyl groups from target substrates. CD38 and SARM1 generate ADPR/cADPR, which are important for second messenger signaling pathways. All figures were generated using BioRender.com.</p>
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<p>ALS pathophysiology and the effect of targeted interventions involving NAD<sup>+</sup> metabolism. Treating ALS models with therapeutic interventions altering NAD<sup>+</sup> metabolism ameliorates many disease-related impairments. Mitochondrial dysfunction, oxidative stress response, activation of glial cells, and protein mislocalization, all of which have been hypothesized as being involved in the development of ALS disease, are corrected from these interventions. Additionally, NMJ innervation and function, sites affected early during ALS development, are improved.</p>
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21 pages, 925 KiB  
Review
From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis
by Marina Hernan-Godoy and Caroline Rouaux
Cells 2024, 13(11), 967; https://doi.org/10.3390/cells13110967 - 3 Jun 2024
Cited by 1 | Viewed by 1926
Abstract
The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute [...] Read more.
The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual’s lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>Genetic and environmental contributions to ALS. (<b>A</b>). Whether sporadic or familial, ALS arises from the combination of genetic susceptibility and environmental factors. (<b>B</b>). Different models are proposed to explain how genetic and environmental interactions may lead to disease onset. (<b>C</b>). Schematic representations of the molecular cascade leading to cellular toxicity in ALS.</p>
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<p>One-carbon metabolism and its impairments in ALS. ALS is associated with alterations of the folate and methionine cycles, such as reported polymorphisms of genes coding for key enzymes (purple), modified levels of metabolites (red), or altered neuronal functions that could indirectly arise from the production of toxic metabolites (orange).</p>
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17 pages, 2089 KiB  
Review
Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies
by Anna Roshani Dashtmian, Fereshteh B. Darvishi and William David Arnold
Cells 2024, 13(11), 928; https://doi.org/10.3390/cells13110928 - 28 May 2024
Viewed by 2317
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2–5 years after disease onset. While ALS can occur in younger individuals, [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2–5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>Comparison of Amyotrophic Lateral Sclerosis (ALS) with age-related decline of the neuromuscular system and with other age-related neurodegenerative disorders (Alzheimer’s Disease (AD) and Parkinson’s Disease (PD)). (<b>A</b>) Increased ALS incidence coincides with onset of grip strength decline in the general population during aging. (<b>B</b>) ALS demonstrates a divergent relationship with age as compared with AD and PD. Panel A is based on previously published data [<a href="#B41-cells-13-00928" class="html-bibr">41</a>,<a href="#B42-cells-13-00928" class="html-bibr">42</a>]. Panel B is based on previously published data [<a href="#B42-cells-13-00928" class="html-bibr">42</a>,<a href="#B48-cells-13-00928" class="html-bibr">48</a>,<a href="#B49-cells-13-00928" class="html-bibr">49</a>].</p>
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<p>Schematic representation of aging signatures in ALS and targeting cellular senescence with senolytic agents as a potential therapeutic approach. Senolytic drugs can selectively target key proteins and apoptotic signaling molecules, effectively eliminating senescent cells and diminishing the senescence-associated secretory phenotype (SASP), along with its associated consequences. Black arrows represent activation. Red blunt-ended lines represent inhibition. PI3K: phosphoinositide 3-kinase, AKT: serine/threonine kinase Akt (also known as protein kinase B or PKB), mTOR: mammalian target of rapamycin, ROS: reactive oxygen species. (Figure created using Biorender).</p>
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22 pages, 420 KiB  
Review
Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis
by Lien Nguyen
Cells 2024, 13(11), 888; https://doi.org/10.3390/cells13110888 - 21 May 2024
Cited by 3 | Viewed by 3184
Abstract
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of [...] Read more.
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
20 pages, 2650 KiB  
Review
Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis
by Andrea Salzinger, Vidya Ramesh, Shreya Das Sharma, Siddharthan Chandran and Bhuvaneish Thangaraj Selvaraj
Cells 2024, 13(10), 792; https://doi.org/10.3390/cells13100792 - 7 May 2024
Cited by 2 | Viewed by 2653
Abstract
The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately [...] Read more.
The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>Schematic of dysfunctions of the cortico-motor system in amyotrophic lateral sclerosis. (<b>A</b>) UMNs in the motor cortex synapse with LMNs in the spinal cord via the corticospinal tract. This circuit degenerates in ALS with patients exhibiting loss of cortical neurons and dendritic and synaptic degeneration. Moreover, changes in neuronal physiology have been observed such as cortical hyperexcitability and reduced cortical inhibition. (<b>B</b>) LMNs in the anterior horn of the spinal cord are particularly vulnerable to degeneration in ALS. Further, altered excitability, dysregulated AMPAR subunit expression, glutamate-mediated excitotoxicity, and degeneration of dendritic spines have been observed in these LMNs. In addition, astrocytes, oligodendrocytes, and microglia (glial cells) undergo functional changes in ALS. (<b>C</b>) LMNs connect to the skeletal muscle via the neuromuscular junction (NMJ) which is denervated early during the disease progression. Initially, surviving LMNs reinnervate orphaned muscle by compensatory axonal sprouting, clinically evidenced by altered fasciculations. Ultimately, muscle fibres are fully denervated. Created with BioRender.com.</p>
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<p>Organoid models of the cortico-motor system. The last decade has seen the emergence of several organoid models of the corticomotor circuit. Human stem cell-derived organoid systems can be generated to model certain aspects of the cerebral cortex, spinal cord, and muscle. Most 3D models generate the primary neural cell types, neuronal and glial progenitor, excitatory and inhibitory neurons, astrocytes and oligodendrocytes. Neuromuscular organoids may contain schwann cells, which are essential for neuromuscular junction maintenance. The generation of assembloid models has progressed the field allowing the study of complex neuronal circuits by assembling region-specific organoids. With increasing interest, researchers aim to incorporate other resident CNS cells such as microglia and vasculature in organoids and, more recently, in assembloids [<a href="#B83-cells-13-00792" class="html-bibr">83</a>,<a href="#B84-cells-13-00792" class="html-bibr">84</a>,<a href="#B85-cells-13-00792" class="html-bibr">85</a>]. Created with BioRender.com.</p>
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16 pages, 1583 KiB  
Review
ALS’ Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis
by Paulien H. Smeele, Giuliana Cesare and Thomas Vaccari
Cells 2024, 13(2), 178; https://doi.org/10.3390/cells13020178 - 17 Jan 2024
Cited by 4 | Viewed by 2895
Abstract
Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin–proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell [...] Read more.
Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin–proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>DPRs as targets and disruptors of cellular clearance pathways. (<b>A</b>) C9-associated DPRs are targeted for degradation by the ubiquitin–proteasome system (UPS) and the autophagy pathway. (<b>B</b>) DPRs impair the UPS by directly interacting with and inhibiting the 26S proteasome. (<b>C</b>) DPRs (and repeat RNAs) disrupt the autophagy pathway reducing the nuclear translocation of TFEB, the master transcriptional regulator of autophagy genes (CLEAR network). (<b>D</b>) G4C2-induced impairment in lysosome function may aid the cell-to-cell transmission of DPRs via endocytosis.</p>
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<p>DPRs induce toxicity by upsetting stress responses. (<b>A,B</b>) DPR accumulation induces ER stress via PERK and other kinases, ultimately decreasing translation as a compensatory mechanism. (<b>C</b>) The induction of ER stress by DPRs promotes RAN translation. (<b>D</b>) DPRs interact directly with the ribosome blocking polypeptide formation. (<b>E</b>) DPRs indirectly stimulate the formation of SGs. (<b>F</b>) (some) DPRs are subjected to LLPS transitions and might directly alter SG dynamics.</p>
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<p>Interplay between protein homeostasis pathways as a potential amplifier of DPR toxicity. (<b>A</b>) DPR-associated inhibition of the proteasome may be a trigger of ER stress, which in turn leads to the increased RAN translation of G4C2 transcripts. (<b>B</b>) DPR-induced ER stress leads to the formation of stress granules (SGs), which in turn may lead to the increased aggregation of DPRs. (<b>C</b>) DPR-associated inhibition of autophagy may lead to the reduced clearance of SGs. Conversely, DPR-associated SGs contribute to the disruptions in the nuclear pore complex (NPC), which may further inhibit the initiation of autophagy.</p>
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23 pages, 1720 KiB  
Review
The Role of c-Abl Tyrosine Kinase in Brain and Its Pathologies
by Helena Motaln and Boris Rogelj
Cells 2023, 12(16), 2041; https://doi.org/10.3390/cells12162041 - 10 Aug 2023
Cited by 10 | Viewed by 2950
Abstract
Differentiated status, low regenerative capacity and complex signaling make neuronal tissues highly susceptible to translating an imbalance in cell homeostasis into cell death. The high rate of neurodegenerative diseases in the elderly population confirms this. The multiple and divergent signaling cascades downstream of [...] Read more.
Differentiated status, low regenerative capacity and complex signaling make neuronal tissues highly susceptible to translating an imbalance in cell homeostasis into cell death. The high rate of neurodegenerative diseases in the elderly population confirms this. The multiple and divergent signaling cascades downstream of the various stress triggers challenge researchers to identify the central components of the stress-induced signaling pathways that cause neurodegeneration. Because of their critical role in cell homeostasis, kinases have emerged as one of the key regulators. Among kinases, non-receptor tyrosine kinase (Abelson kinase) c-Abl appears to be involved in both the normal development of neural tissue and the development of neurodegenerative pathologies when abnormally expressed or activated. However, exactly how c-Abl mediates the progression of neurodegeneration remains largely unexplored. Here, we summarize recent findings on the involvement of c-Abl in normal and abnormal processes in nervous tissue, focusing on neurons, astrocytes and microglial cells, with particular reference to molecular events at the interface between stress signaling, DNA damage, and metabolic regulation. Because inhibition of c-Abl has neuroprotective effects and can prevent neuronal death, we believe that an integrated view of c-Abl signaling in neurodegeneration could lead to significantly improved treatment of the disease. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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Graphical abstract

Graphical abstract
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<p>c-Abl signaling involved in multiple cellular processes. Schematic illustrating the different Abl signaling pathways discussed in the following text and highlighting the correlation with the abnormal processes associated with neurodegenerative diseases.</p>
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39 pages, 2810 KiB  
Review
Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy
by Eva Bagyinszky, John Hulme and Seong Soo A. An
Cells 2023, 12(15), 1948; https://doi.org/10.3390/cells12151948 - 27 Jul 2023
Cited by 5 | Viewed by 3942
Abstract
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5–10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder [...] Read more.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5–10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially “at risk” individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible. Full article
(This article belongs to the Special Issue Genetics and Pathomechanisms of Amyotrophic Lateral Sclerosis (ALS))
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<p>Pathological processes that may contribute to neuronal death in MND and ALS.</p>
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<p>Mutant <span class="html-italic">SOD1</span> and ALS-related pathways, adapted from Refs. [<a href="#B20-cells-12-01948" class="html-bibr">20</a>,<a href="#B21-cells-12-01948" class="html-bibr">21</a>,<a href="#B27-cells-12-01948" class="html-bibr">27</a>].</p>
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<p>TARDBP mechanisms in ALS progression, adapted from Refs. [<a href="#B46-cells-12-01948" class="html-bibr">46</a>,<a href="#B47-cells-12-01948" class="html-bibr">47</a>,<a href="#B48-cells-12-01948" class="html-bibr">48</a>].</p>
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<p>Domains of <span class="html-italic">FUS</span> gene and possible mechanisms of FUS mutations, adapted from Refs. [<a href="#B50-cells-12-01948" class="html-bibr">50</a>,<a href="#B51-cells-12-01948" class="html-bibr">51</a>].</p>
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<p>Activation of neurodegenerative pathways resulting from <span class="html-italic">C9orf72</span> repeat expansion. Repeat expansion could be associated with loss-of function (LOF) mechanism, called haploinsufficiency. Gain-of function (GOF)mechanisms may also be related with G4C2 expansion, such as RNA-Binding Proteins (RBP) sequestration (leading to alternative splicing and impaired RNA transport/translation). Additional GOF pathway could be an alternative START codon generation and Repeat Associated Non-AUG (RAN) translation, leading to dipeptide repeat (DPR) production, accumulation and toxicity. The figure was adapted from Refs. [<a href="#B66-cells-12-01948" class="html-bibr">66</a>,<a href="#B67-cells-12-01948" class="html-bibr">67</a>,<a href="#B68-cells-12-01948" class="html-bibr">68</a>,<a href="#B69-cells-12-01948" class="html-bibr">69</a>,<a href="#B70-cells-12-01948" class="html-bibr">70</a>,<a href="#B71-cells-12-01948" class="html-bibr">71</a>,<a href="#B72-cells-12-01948" class="html-bibr">72</a>,<a href="#B73-cells-12-01948" class="html-bibr">73</a>].</p>
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<p>Potential biological processes/functions affected by common and rare ALS-related genes during ALS progression [<a href="#B18-cells-12-01948" class="html-bibr">18</a>,<a href="#B74-cells-12-01948" class="html-bibr">74</a>]. The differently colored edges may represent the proterin-protein associations. The light blue means, association was verified from curated databases. Pink means, interactions were proven experimentally. The darker green means “gene neighbourhood”. Red means possible gene fusion. Darker blue means gene co-occurrence. Light green means “text mining” or possible association from literature. The black means that the genes may interact through co-expression. The purple edge means that these genes may share homology. Network analyses were performed by STRING software version 11.5 (<a href="https://string-db.org/" target="_blank">https://string-db.org/</a>, accessed on 20 July 2023).</p>
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