Mechanistic Insights of Astrocyte-Mediated Hyperactive Autophagy and Loss of Motor Neuron Function in SOD1L39R Linked Amyotrophic Lateral Sclerosis

Rajpurohit, Chetan Singh; Kumar, Vivek; Cheffer, Arquimedes; Oliveira, Danyllo; Ulrich, Henning; Okamoto, Oswaldo Keith; Zatz, Mayana; Ansari, Uzair Ahmad; Khanna, Vinay K.; Pant, Aditya B.

doi:10.1007/s12035-020-02006-0

Cited by 21 publications

(22 citation statements)

References 60 publications

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“…The protein component of SGs examined in these studies includes G3BP1, TIA-1, hnRNPA1, TDP-43, PABP-1, FUS, TIAR, eIF4A3, eIF4A1, eIF3, eIF4G, UPF1, UPF3b, HuR, ANXA11, Pur-alpha, which are also summarized in Figure 3 . The cell lines used in this study carry missense mutations in SOD1 (Gal et al, 2016 ; Rajpurohit et al, 2020 ), TARDBP (Orrù et al, 2016 ; Loginov et al, 2018 ; Ratti et al, 2020 ), FUS (Japtok et al, 2015 ; Lenzi et al, 2015 ; Daigle et al, 2016 ; Ichiyanagi et al, 2016 ; Lim et al, 2016 ; Lo Bello et al, 2017 ; Kamelgarn et al, 2018 ; Arenas et al, 2020 ), TDP-43 (Kreiter et al, 2018 ; Loginov et al, 2018 ; Feneberg et al, 2020 ) and ANXA11 (Gieseler et al, 2019 ) genes and frameshift mutations in FUS (Japtok et al, 2015 ; Lim et al, 2016 ) gene and hexanucleotide repeat expansion mutations in C9ORF72 gene (Dafinca et al, 2016 ; Loginov et al, 2018 ; Ratti et al, 2020 ). Studies were conducted in the United States, Italy, Germany, France, Japan, South Korea, India and the United Kingdom.…”

Section: Resultsmentioning

confidence: 99%

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Stress Granules and Neurodegenerative Disorders: A Scoping Review

Asadi

Moslehian

Sabaie

et al. 2021

Front. Aging Neurosci.

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Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted until December 2020. Publications were screened independently by two reviewers and quantitative and qualitative analysis was performed on the extracted data. Bioinformatics analysis was used to plot the network and predict interprotein interactions. In addition, GO analysis was performed. A total of 48 articles were identified that comply the inclusion criteria. Most studies on neurodegenerative diseases have been conducted on ALS, AD, and FTD using human post mortem tissues. Human derived cell line studies have been used only in ALS. A total 29 genes of protein components of SGs have been studied, the most important of which are TDP-43, TIA-1, PABP-1. Bioinformatics studies have predicted 15 proteins to interact with the protein components of SGs, which may be the constituents of SGs. Understanding the interactions between SGs and pathological aggregations in neurodegenerative diseases can provide new targets for treatment of these disorders.

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Section: Resultsmentioning

confidence: 99%

“…Mutations that occur in SOD1 can also affect the dynamics of SGs. The mutant types SOD1-L144F (Gal et al, 2016 ) and SOD1-L39R (Rajpurohit et al, 2020 ) colocalize with G3BP1 in fibroblast-derived motor neurons, whereas SOD1-WT does not colocalize with SGs (Gal et al, 2016 ; Rajpurohit et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Stress Granules and Neurodegenerative Disorders: A Scoping Review

Asadi

Moslehian

Sabaie

et al. 2021

Front. Aging Neurosci.

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“…The effect of other mutations, classified with the PS3_Moderate or PS3_Supporting criterion, was evaluated by functional in vitro studies [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ] assessing the correlation between the specific genetic alteration and the modification of oxidative stress, mitochondrial and cellular metabolism in different clinical phenotypes ( Supplementary Table S3 ). PS3 with moderate weight was attributed to 20 (62.5%) variants: 10 (50%) were classified as likely pathogenic, while the remaining 10 (50%) as pathogenic.…”

Section: Resultsmentioning

confidence: 99%

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

Ruffo

Perrone

Conforti

2022

Genes

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Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.

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“…As discussed above, the regional and functional diversity of astrocytes in both the brain and spinal cord underlies specialized interactions of specific astrocyte populations with particular neuronal neighbors (Hochstim et al, 2008;Tsai et al, 2012;Bayraktar et al, 2014;Molofsky et al, 2014;Kelley et al, 2018a;Mishra et al, 2020), underscoring the importance of accounting for astrocyte heterogeneity when studying the involvement of astrocytes in neurodegenerative diseases such as ALS. Up to date, hiPSC-derived astrocyte cultures used to model ALS pathophysiology have usually included a mix of multiple types of astrocytes (e.g., Hall et al, 2017;Madill et al, 2017;Qian et al, 2017;Tyzack et al, 2017;Kelley et al, 2018a;Birger et al, 2019;Varcianna et al, 2019;Rajpurohit et al, 2020;Smethurst et al, 2020;Zhao et al, 2020). This situation is not ideal to address the complexity of astrocyte dysfunction, and motor neuronastrocyte communication, in ALS, especially when taking into consideration that multiple motor neuron subtypes are affected in ALS.…”

Section: Taking Cellular Heterogeneity Into Consideration When Deriving Astrocytes From Human Induced Pluripotent Stem Cells For Als Modementioning

confidence: 99%

“…This would involve a thorough characterization of DV NPC marker expression, in order to select for the NPCs that would be predicted to give rise to astrocyte subtypes with the desired molecular properties, followed by validation of differentiated astrocytes using scRNAseq approaches. This has not been case in the field of ALS thus far, since common astrocyte differentiation protocols used for ALS modeling have usually relied on similar SHH and RA signaling conditions (e.g., Hall et al, 2017;Madill et al, 2017;Qian et al, 2017;Tyzack et al, 2017;Kelley et al, 2018b;Birger et al, 2019;Varcianna et al, 2019;Rajpurohit et al, 2020;Smethurst et al, 2020;Zhao et al, 2020).…”

Section: Dorsal or Ventral Astrocytes?mentioning

confidence: 99%

Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells

Stifani

2021

Front. Cell. Neurosci.

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Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.

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Mechanistic Insights of Astrocyte-Mediated Hyperactive Autophagy and Loss of Motor Neuron Function in SOD1L39R Linked Amyotrophic Lateral Sclerosis

Cited by 21 publications

References 60 publications

Stress Granules and Neurodegenerative Disorders: A Scoping Review

Stress Granules and Neurodegenerative Disorders: A Scoping Review

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells

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