RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

Fan, Alexander C.; Leung, Anthony K.L.

doi:10.1007/978-3-319-29073-7_11

Cited by 48 publications

(47 citation statements)

References 174 publications

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“…Until mRNA translation, they sequester mRNA into membrane-less organelles called ribonucleoprotein granules (RNPs). There are two main types of RNPs: P-bodies and stress granules (Fan and Leung, 2016 ). Stress granules are formed in the cell under conditions of high stress and act to repress translation initiation of the mRNAs.…”

Section: Autophagy: Converging Point For Other Pathogenic Mechanismsmentioning

confidence: 99%

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand

Ramesh

Pandey

2017

Front. Mol. Neurosci.

129

100

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results from the loss of upper and lower motor neurons. One of the key pathological hallmarks in diseased neurons is the mislocalization of disease-associated proteins and the formation of cytoplasmic aggregates of these proteins and their interactors due to defective protein quality control. This apparent imbalance in the cellular protein homeostasis could be a crucial factor in causing motor neuron death in the later stages of the disease in patients. Autophagy is a major protein degradation pathway that is involved in the clearance of protein aggregates and damaged organelles. Abnormalities in autophagy have been observed in numerous neurodegenerative disorders, including ALS. In this review, we discuss the contribution of autophagy dysfunction in various in vitro and in vivo models of ALS. Furthermore, we examine the crosstalk between autophagy and other cellular stresses implicated in ALS pathogenesis and the therapeutic implications of regulating autophagy in ALS.

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Section: Autophagy: Converging Point For Other Pathogenic Mechanismsmentioning

confidence: 99%

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand

Ramesh

Pandey

2017

Front. Mol. Neurosci.

129

100

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“…Importantly, the glutamine‐rich prion‐related domain (PRD) of TIA‐1 is responsible for the induction of SGs, the formation of self‐aggregates and recruitment of TIA‐1 to SGs (Gilks et al., ). Intrinsically disordered regions (IDRs), by mediating low‐affinity protein–protein interactions, have emerged as essential mechanisms that form SGs, and PRD is a class of IDRs that is essential to SG physiology with implications for neurological diseases (Fan & Leung, ). The amino acid sequence of Rnc1 revealed the presence of two disordered regions (Supporting Information Figure S2).…”

Section: Discussionmentioning

confidence: 99%

Distinct modes of stress granule assembly mediated by the KH‐type RNA‐binding protein Rnc1

et al. 2018

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We have previously identified the KH-type RNA-binding protein Rnc1 as an important regulator of the posttranscriptional expression of the MAPK phosphatase Pmp1 in fission yeast. Rnc1 localization in response to stress has not been elucidated thus far. Here, we report the dual roles of Rnc1 in assembly of stress granules (SGs), nonmembranous cytoplasmic foci composed of messenger ribonucleoproteins. Rnc1 can localize to poly(A)-binding protein (Pabp)-positive SGs upon various stress stimuli, including heat shock (HS) and arsenite treatment. Furthermore, Rnc1 deletion results in decreased SGs, indicating that Rnc1 is a new component and a regulator of SGs. Notably, Rnc1 translocates to the dot-like structures faster than Pabp, and this stress-induced Rnc1 translocation does not require its RNA-binding ability, as the Rnc1 mutant protein with impaired RNA-binding activity forms dots rather more efficiently than the wild-type Rnc1 upon HS. Interestingly, in the absence of stress, Rnc1 overproduction induced massive aggregation of Pabp-positive SGs and eIF2α phosphorylation. In clear contrast, overproduction of the Rnc1 mutant failed to induce Pabp aggregation and eIF2α phosphorylation, indicating that Rnc1 overproduction-induced SG assembly requires Rnc1 RNA-binding activity. Collectively, Rnc1 regulates SG assembly, dependently or independently of its RNA-binding activity.

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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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RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

Cited by 48 publications

References 174 publications

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand

Distinct modes of stress granule assembly mediated by the KH‐type RNA‐binding protein Rnc1

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

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