Exploration of Nanonutraceuticals in Neurodegenerative Diseases
Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani in Nutraceuticals and Dietary Supplements, 2020
Protein toxicity is a unifying feature of both sporadic and familial cases of neurodegeneration. Neuronal degeneration causes immense cellular stress and results in the formation of stress granules. Electrostatic interactions between proteins facilitate liquid–liquid phase separation causing formation of stress granules (Chung et al., 2018). Two leading neuropathological changes of AD are the neurofibrillary tangles made of paired helical filaments containing the microtubule-associated protein, tubulin-associated unit (Tau) accumulating in neuronal perikarya and extracellular diffuse amyloid deposits containing amyloid peptide-forming neuritic senile plaques (Bloom, 2014; Giacobini and Gold, 2017). Inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules are the pathways to be explored for development of new therapeutics. Amyloid β (Aβ) peptides are 39–43 amino acid residue peptides derived from the sequential proteolytic enzymatic action of β-secretase and γ-secretase on transmembrane amyloid precursor protein. Aβ deposition and diffused plaque formation causes local microglial activation, cytokine release, reactive astrocytosis, and a multiprotein inflammatory response.
Approach to Vacuolar Myopathy
Maher Kurdi in Neuromuscular Pathology Made Easy, 2021
Granulophagy defect due to cargo degradation is commonly associated with inclusion body myositis (IBM), and it causes cellular accumulation of stress granules. Moreover, failure of autophagy induction with no formation of autophagosome was detected in some cases of muscular dystrophy as well as centronuclear myopathies. An accumulation of undigested cargo also can cause autophagy flux defect, which results in autophagic myopathies (Figure 15.1).
SILAC-based quantitative proteomics identifies size-dependent molecular mechanisms involved in silver nanoparticles-induced toxicity
Published in Nanotoxicology, 2019
M. N. Fernández, R. Muñoz-Olivas, J. L. Luque-Garcia
As another defense mechanism against cellular damage induced by AgNPs, we also found some altered proteins that suggest activation of the integrated stress response (ISR) pathway. This pathway is activated in eukaryotic cells in response to a range of physiological changes and different pathological conditions to restore cellular homeostasis (Pakos-Zebrucka et al. 2016). The activation of the ISR often promotes the formation of ribonucleoprotein aggregates called stress granules. These stress granules help the cell to conserve energy and to increase the availability of the translation machinery for stress-related gene expression; thus protecting cells from apoptosis. Supporting our hypothesis, we found upregulation of RhoA (RSILAC = +1.32) in cells exposed to AgNP10, which is a protein that usually appears overexpressed under stress and is required for the formation of stress granules (Tsai and Wei 2010). In addition, stress granules are composed of mRNA and RNA binding proteins (Shao et al. 2017) including CAPRIN1 (RSILAC = +1.39), overexpressed upon AgNP10 exposure, and SND1 (RSILAC = +1.80), found in cells exposed to AgNP60. Another translation and initiation component found in stress granules, eIF4G1, was also found overexpressed in both AgNP10 (RSILAC = +1.65) and AgNP60 (RSILAC = +1.46) exposed cells (Rozelle et al. 2014).
Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials
Published in Expert Opinion on Emerging Drugs, 2020
Andrea Barp, Francesca Gerardi, Andrea Lizio, Valeria Ada Sansone, Christian Lunetta
There was a shift in focus to RNA dysregulation as a key of pathological process in ALS with the identification of disease-causing variations in RNA-binding protein genes, TARDBP [38], FUS [39,40], hnRNPA1 [41], MATR3 [42], TAF15 [43], and TIA1 [44]. Moreover, a variety of RNA binding factors are found sequestered in association with the hexanucleotide repeat expansion in the C9orf72 gene transcript [45–47]. Indeed, a misregulated splicing has been described in the cerebellum and frontal cortex of ALS patients with C9orf72 repeat expansion, as well as in sporadic patients [48]. RNA-binding proteins are involved in several aspects of RNA metabolism, including splicing, transcription, transport, translation, and storage in stress granules. These discoveries have led to an increased interest in the role of RNA metabolism in neurodegenerative diseases.
Understanding host responses to equine encephalitis virus infection: implications for therapeutic development
Published in Expert Review of Anti-infective Therapy, 2022
Kylene Kehn-Hall, Steven B. Bradfute
Stress granules, which contain translation initiation factors, non-translated RNAs, and ribosomal components, are formed in eukaryotic cells in response to stress, such as viral infection [73]. Their formation coincides with translational inhibition. During alphavirus infections, stress granule formation is suppressed by nsP3; nsP3 interacts with stress granule proteins to repurpose them to assist with viral replication [74,75]. nsP3 from the Old World alphaviruses, SINV and chikungunya virus (CHIKV), interact with GTPase-activating protein (SH3 domain)-binding protein (G3BP) family members, whereas VEEV nsP3 was found in complex with Fragile X syndrome (FXR) family members [76,77]. nsP3 interaction with G3BP and FXR proteins is mediated through the nsP3 hypervariable domains (HVDs) and these complexes assist in the assembly of viral replication complexes (vRCs). Interestingly, EEEV nsP3 interacts with both G3BP and FXR family members and utilizes both for efficient viral replication [78]. Out of 20 alphaviruses tested (including WEEV and EEEV), all nsP3 proteins except salmonid alphavirus (SAV), Tai Forest virus (TAFV) and VEEV colocalize with G3BP [79]. This indicates that among the encephalitic equine alphaviruses, VEEV is unique in its lack of G3BP binding.
Related Knowledge Centers
- Cell Biology
- Protein
- Rna
- Stress
- Cell Nucleus
- Biomolecular Condensate
- Cytosol
- Cell
- Translation
- Endoplasmic Reticulum