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: 30 September 2024 | Viewed by 6799

Special Issue Editor


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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

Published Papers (5 papers)

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Review

22 pages, 631 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 (registering DOI) - 21 May 2024
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
Viewed by 465
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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17 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
Viewed by 1454
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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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 6 | Viewed by 1638
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

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
Viewed by 2492
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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