Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia

Rossi, Simona; Cozzolino, Mauro

doi:10.3390/cells10113005

Cited by 7 publications

(4 citation statements)

References 168 publications

(214 reference statements)

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“…Since motor neurons have very long axons, they are more susceptible to axonal retraction and axonal transport dysfunctions than other neurons, further explaining the selective vulnerability in ALS pathogenesis ( Robberecht and Philips, 2013 ). Finally, abnormal glial activation (popularly defined as “gliosis”) is extensively found throughout the brain and spinal cord of both fALS and sALS cases ( Agbas et al, 2021 ; Rossi and Cozzolino, 2021 ), and especially the involvement of astrocytes will be discussed later in this review.…”

Section: Introductionmentioning

confidence: 99%

Why should we care about astrocytes in a motor neuron disease?

Dittlau

Bosch

2023

Front. Mol. Med

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.

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Section: Introductionmentioning

confidence: 99%

Why should we care about astrocytes in a motor neuron disease?

Dittlau

Bosch

2023

Front. Mol. Med

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“…[10] In the central nervous system, microglia are innate immune cells that participate in neuroinflammation and contribute significantly to the development of ALS. [11][12][13] So, to inhabit the activation of microglia might be another mechanism of SS treating ALS.…”

Section: Introductionmentioning

confidence: 99%

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Tang,

Zhan,

Yang

et al. 2023

Medicine

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Semen Strychni (SS), known as an agonist of central nervous system, is a traditional herb widely used in treating amyotrophic lateral sclerosis (ALS) in small doses to relieve muscle weakness and improve muscle strength. However, the potential mechanisms and the main components of SS in treating ALS remain unclear. To explore the underlying mechanism of SS in treating ALS based on network pharmacology and molecular docking. The active components of SS were obtained using TCMSP, Herb, ETCM, and BATMAN-TCM. The targets of SS were gained from PharmMapper. The targets of ALS were searched on Genecards, Drugbank, DisGeNET, OMIM, TTD and GEO database. After obtaining the coincidence targets, we submitted them to the STRING database to build a protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed subsequently. The active components and targets were further investigated using molecular docking technology. 395 targets of SS and 1925 targets of ALS were obtained with 125 common targets. The protein-protein interaction analysis indicated that SRC, AKT1, MAPK1, EGFR, and HSP90AA1 received the higher degree value and were considered the central genes. The Ras, PI3K-Akt, and MAPK signaling pathway could be involved in the treatment of ALS. Brucine-N-oxide obtained the lowest binding energy in molecular docking. This study explored the mechanism of SS in the treatment of ALS and provides a new perspective for future study. However, further experimental studies are needed to validate the therapeutic effect.

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“…The major mechanisms of neurodegeneration in ALS proposed in the past decades include, but are not limited to, the following pathways: oxidative damage, 5 abnormal protein aggregation, [6][7][8] glutamate-induced excitotoxicity, 9,10 neuroinflammation, 11,12 mitochondrial dysfunction [13][14][15][16] , and RNA dysregulation [17][18][19] . Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Modulation of Autophagy Prevents Mutant SOD1^G93AInduced Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

Yan

Yacipi

et al. 2022

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the progressive loss of both upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, there are only two drugs, Riluzole (Rilutek) and Edaravone (Radicava), approved by FDA for ALS treatment. These two drugs are very expensive with only a few months of life extension. So far, there is no cure for ALS. Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. The disturbance in protein homeostasis may contribute to the onset and progression of ALS. Autophagy plays an important role in degrading misfolded proteins and thereby preventing their aggregation. Pharmacological manipulation of autophagy has been proposed as a new therapeutic approach for treating ALS. IADB, a novel indole alkaloid derivative, has been reported to exert mitochondrial protection and cardioprotection through its autophagy-modulating potential. In our present study, we attempted to examine whether IADB has therapeutic potential in SOD1G93A-associated experimental models of ALS. We found that IADB could promote the clearance of SOD1G93A aggregates and reduce the overproduction of mitochondrial reactive oxygen species (ROS) in motor neuron-like NSC-34 cells transfected with SOD1G93A. We further examined the IADB in a mouse model of ALS. Administration of IADB started at the age of 55 days until the end stage of the disease. IADB treatment significantly increased LC3-II levels and decreased human SOD1 levels and p62 expression in the spinal cords of SOD1G93A mice, suggesting that IADB treatment could induce autophagy activation and promote clearance of mutant SOD1 aggregates in SOD1G93A mice. Moreover, IADB treatment could alleviate the activation of microglia and astrocytes and mitochondrial oxidative damage in the spinal cord of SOD1G93A mice. Finally, we demonstratedthat IADB treatment could improve motor performance and delay the onset and progression of the disease in a mouse model of ALS. The neuroprotective effects of IADB may mainly originate from its autophagy-promoting property.

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Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia

Cited by 7 publications

References 168 publications

Why should we care about astrocytes in a motor neuron disease?

Why should we care about astrocytes in a motor neuron disease?

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Pharmacological Modulation of Autophagy Prevents Mutant SOD1^G93AInduced Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

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Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia

Cited by 7 publications

References 168 publications

Why should we care about astrocytes in a motor neuron disease?

Why should we care about astrocytes in a motor neuron disease?

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Pharmacological Modulation of Autophagy Prevents Mutant SOD1G93AInduced Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

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Pharmacological Modulation of Autophagy Prevents Mutant SOD1^G93AInduced Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)