Stress Granules and ALS: A Case of Causation or Correlation?

Fernandes, Nikita; Eshleman, Nichole; Buchan, J. Ross

doi:10.1007/978-3-319-89689-2_7

Cited by 41 publications

(48 citation statements)

References 246 publications

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“…As for α‐Syn, we found that autophagy blockage by Atg5 knockdown increases PIC components in exosomes . Moreover, in a pathological context, amyotrophic lateral sclerosis is a neurodegenerative disease characterized by neurons presenting cytoplasmic aggregates whose formation is suspected to be facilitated by SG assembly . The prionoid TDP‐43 (transactive response DNA‐binding protein) is a nuclear RNA binding protein whose turnover and toxicity has been shown to depend on the endocytosis pathway .…”

Section: Exosomes and Homeostasismentioning

confidence: 87%

“…PICs contain stalled mRNA that can be reused to reinitiate translation upon stress release. If stress persists, SG clearance has been demonstrated to partly involve autophagy by a so‐called granulophagy mechanism . Interestingly, specific mRNAs have been shown to be the preferential targets of translational arrest, and were highly represented in a seminal paper describing exosomal mRNAs .…”

Section: Exosomes and Homeostasismentioning

confidence: 99%

“…If stress persists, SG clearance has been demonstrated to partly involve autophagy by a socalled granulophagy mechanism. 155 Interestingly, specific mRNAs have been shown to be the preferential targets of translational arrest, 156 and were highly represented in a seminal paper describing exosomal mRNAs. 152 As for α-Syn, 53 we found that autophagy blockage by Atg5 knockdown increases PIC components in exosomes.…”

Section: Nucleic Acidsmentioning

confidence: 99%

“…131 Moreover, in a pathological context, amyotrophic lateral sclerosis is a neurodegenerative disease characterized by neurons presenting cytoplasmic aggregates whose formation is suspected to be facilitated by SG assembly. 155 The prionoid TDP-43 (transactive response DNAbinding protein) is a nuclear RNA binding protein whose turnover and toxicity has been shown to depend on the endocytosis pathway. 157 When mutated or under stress conditions, TDP-43 translocates to the cytoplasm and constitutes a major component of these aggregates.…”

Section: Nucleic Acidsmentioning

confidence: 99%

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Exosomes: Revisiting their role as “garbage bags”

Vidal

2019

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118

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In recent years, the term “extracellular vesicle” (EV) has been used to define different types of vesicles released by various cells. It includes plasma membrane‐derived vesicles (ectosomes/microvesicles) and endosome‐derived vesicles (exosomes). Although it remains difficult to evaluate the compartment of origin of the two kinds of vesicles once released, it is critical to discriminate these vesicles because their mode of biogenesis is probably directly related to their physiologic function and/or to the physio‐pathologic state of the producing cell. The purpose of this review is to specifically consider exosome secretion and its consequences in terms of a material loss for producing cells, rather than on the effects of exosomes once they are taken up by recipient cells. I especially describe one putative basic function of exosomes, that is, to convey material out of cells for off‐site degradation by recipient cells. As illustrated by some examples, these components could be evacuated from cells for various reasons, for example, to promote “differentiation” or enhance homeostatic responses. This basic function might explain why so many diseases have made use of the exosomal pathway during pathogenesis.

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Section: Exosomes and Homeostasismentioning

confidence: 87%

Section: Exosomes and Homeostasismentioning

confidence: 99%

Section: Nucleic Acidsmentioning

confidence: 99%

Section: Nucleic Acidsmentioning

confidence: 99%

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Exosomes: Revisiting their role as “garbage bags”

Vidal

2019

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118

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“…Genetic mutations are commonly observed in RNA-binding proteins such as FUS (e.g. R495X), and overexpression of some ALS-related mutant RNA-binding proteins results in the formation of aggregates enriched in canonical SG components such as G3BP1 and translation initiation factors [58,59]. We hypothesized that the formation of FUS R495X-mediated SG-like aggregates might also be suppressed by nsP3 ADPribosylhydrolase activity.…”

Section: Adp-ribosylhydrolase Activity Of Nsp3 Suppresses the Formatimentioning

confidence: 99%

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Jayabalan

Griffin

Leung

2019

Preprint

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Formation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADPribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1.We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADPribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions. All rights reserved. No reuse allowed without permission. INTRODUCTIONNon-membranous structures are prevalent in cells and critical for cellular functions, including RNA metabolism, embryonic cell fate specification, and neuronal activities [1][2][3]. Although the components of these non-membranous structures are often dynamically exchanged with the surrounding milieu, the compositions of these cellular structures remain distinct [4]. It is, however, unclear how individual components are selectively retained in these non-membranous structures.Stress granules (SGs), one of the best characterized dynamic non-membranous structures, are RNAprotein assemblies formed in response to a variety of environmental cues [3]. In most cases, these environmental cues activate stress-responsive protein kinases that phosphorylate the eukaryotic initiation factor 2 alpha (eIF2α), resulting in the stalling of translation initiation [3]. The sudden influx of untranslated mRNAs is proposed to seed the formation of SGs, where the polynucleotide promotes local concentration of proteins through non-covalent binding [5]. These RNA-binding proteins are highly enriched with low-complexity regions, and emergent data indicate that the nonspecific, weak interactions between these regions are responsible for the condensation of proteins to form higherorder structures, such as microscopically visible SGs [6][7][8]. Depending on the type of stress, the composition of SGs could vary [9], but certain common components, such as Ras GTP-activating protein-binding proteins G3BP1/2, are essential for SG formation [10,11]. Dysregulation of SG assembly/disassembly and mutations in the low-complexity region of specific SG proteins are implicated in the pathogenesis of diseases such as viral infection, cancer and neurodegeneration [1,[12][13][14]. Therefore, understanding the regulatory mechanisms of SG assembly is critical for designing novel th...

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Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno‐associated viral vectors

Merjane

Chung

Patani

et al. 2023

Medicinal Research Reviews

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Despite the devastating clinical outcome of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), its etiology remains mysterious. Approximately 90% of ALS is characterized as sporadic, signifying that the patient has no family history of the disease. The development of an impactful disease modifying therapy across the ALS spectrum has remained out of grasp, largely due to the poorly understood mechanisms of disease onset and progression. Currently, ALS is invariably fatal and rapidly progressive. It is hypothesized that multiple factors can lead to the development of ALS, however, treatments are often focused on targeting specific familial forms of the disease (10% of total cases). There is a strong need to develop disease modifying treatments for ALS that can be effective across the full ALS spectrum of familial and sporadic cases. Although the onset of disease varies significantly between patients, there are general disease mechanisms and progressions that can be seen broadly across ALS patients. Therefore, this review explores the targeting of these widespread disease mechanisms as possible areas for therapeutic intervention to treat ALS broadly. In particular, this review will focus on targeting mechanisms of defective protein homeostasis and RNA processing, which are both increasingly recognized as design principles of ALS pathogenesis. Additionally, this review will explore the benefits of gene therapy as an approach to treating ALS, specifically focusing on the use of adeno‐associated virus (AAV) as a vector for gene delivery to the CNS and recent advances in the field.

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Stress Granules and ALS: A Case of Causation or Correlation?

Cited by 41 publications

References 246 publications

Exosomes: Revisiting their role as “garbage bags”

Exosomes: Revisiting their role as “garbage bags”

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno‐associated viral vectors

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