scholarly journals Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2773
Author(s):  
Hsiao-Chien Ting ◽  
Hui-I Yang ◽  
Horng-Jyh Harn ◽  
Ing-Ming Chiu ◽  
Hong-Lin Su ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Nerve Fiber ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Effects ◽  
Patient Death ◽  
Sporadic Als ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.

scholarly journals The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

2017 ◽  
Vol 9 (391) ◽  
pp. eaaf3962 ◽  
Author(s):  
Keiko Imamura ◽  
Yuishin Izumi ◽  
Akira Watanabe ◽  
Kayoko Tsukita ◽  
Knut Woltjen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
New Drugs ◽  
Small Interfering Rnas ◽  
Altered Expression ◽  
Sporadic Als ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

scholarly journals Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis

Brain ◽  
2020 ◽  
Vol 143 (2) ◽  
pp. 430-440 ◽  
Author(s):  
Phillip Smethurst ◽  
Emmanuel Risse ◽  
Giulia E Tyzack ◽  
Jamie S Mitchell ◽  
Doaa M Taha ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Pathological Feature ◽  
Cell Type ◽  
Sporadic Als ◽  
Cell Type Specific ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.

scholarly journals Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Junmei Wang ◽  
Lydia Tierney ◽  
Ranjeet Mann ◽  
Thomas Lonsway ◽  
Chandler L. Walker
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Lumbar Spinal Cord ◽  
Therapeutic Effects ◽  
Spinal Cord Tissue ◽  
Neuron Loss ◽  
Neuroprotective Therapy ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 μg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.

Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110308
Author(s):  
Fahad Hassan Shah ◽  
Song Ja Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Major Gene ◽  
Dna Binding Protein ◽  
Chemical Affinity ◽  
Drug Candidates ◽  
Medicinal Compounds ◽  
Candidate Drug ◽  
Lateral Sclerosis

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.

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

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.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

scholarly journals Impact of traumatic brain injury on amyotrophic lateral sclerosis: from bedside to bench

2019 ◽  
Vol 122 (3) ◽  
pp. 1174-1185 ◽  
Author(s):  
Colin K. Franz ◽  
Divya Joshi ◽  
Elizabeth L. Daley ◽  
Rogan A. Grant ◽  
Kyriakos Dalamagkas ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Amyotrophic Lateral Sclerosis ◽  
Brain Injury ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Epidemiological Studies ◽  
History Of ◽  
Induced Pluripotent ◽  
Progressive Weakness ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, which manifests clinically as progressive weakness. Although several epidemiological studies have found an association between traumatic brain injury (TBI) and ALS, there is not a consensus on whether TBI is an ALS risk factor. It may be that it can cause ALS in a subset of susceptible patients, based on a history of repetitive mild TBI and genetic predisposition. This cannot be determined based on clinical observational studies alone. Better preclinical models are necessary to evaluate the effects of TBI on ALS onset and progression. To date, only a small number of preclinical studies have been performed, mainly in the superoxide dismutase 1 transgenic rodents, which, taken together, have mixed results and notable methodological limitations. The more recent incorporation of additional animal models such as Drosophila flies, as well as patient-induced pluripotent stem cell-derived neurons, should facilitate a better understanding of a potential functional interaction between TBI and ALS.

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