Tuesday, December 07, 2021 11:00:08 PM
The sigma-1 receptor is a trans-membrane protein. Protein synthesis represents a major metabolic activity of the cell. However, it is affected by aging. In CNS diseases Sigma 1 function is impaired. In Alzheimer's disease, for example, sigma-1 receptor (s1R) expression decreases. The decrease in s-1R expression during AD coincides with an age-related decrease in autophagy. Autophagy plays a key role in the progression of AD pathology.
Anavex has conducted both RNA and whole exome DNA genome sequencing from ANAVEX®2-73-treated patients.
"ANAVEX®2-73 Establishes SIGMAR1 mRNA Predictive Biomarker of Efficacy in Alzheimer’s, Parkinson’s and Rett Syndrome" (From slide 6 Dec 2021 Presentation). Anavex maintains that ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker, which indicates that its drug is inducing a beneficial effect by increasing sigma-1 expression in these CNS diseases. Anavex hopes that the FDA will accept this biomarker (Sigmar 1 mRNA expression) along with all of the other evidence that it will submit with its application for approval of AVXL 2-73.
If AVXL 2-73 increases sigma 1 mRNA expression, this helps to explain its housekeeping function and restoration of homeostasis. See articles cited below.
1. MESSENGER RNA or mRNA
What does mRNA do? mRNA produces instructions to make proteins that may treat or prevent disease....
It’s actually basic human biology.
DNA (deoxyribonucleic acid) is a double-stranded molecule that stores the genetic instructions your body’s cells need to make proteins. Proteins, on the other hand, are the ‘workhorses’ of the body. Nearly every function in the human body – both normal and disease-related – is carried out by one or many proteins.
......
mRNA is just as critical as DNA.
Without mRNA, your genetic code would never get used by your body. Proteins would never get made. And your body wouldn’t – actually couldn’t – perform its functions. Messenger ribonucleic acid, or mRNA for short, plays a vital role in human biology, specifically in a process known as protein synthesis. mRNA is a single-stranded molecule that carries genetic code from DNA in a cell’s nucleus to ribosomes, the cell’s protein-making machinery.
https://www.modernatx.com/mrna-technology/science-and-fundamentals-mrna-technology
2. Multifaceted deregulation of gene expression and protein synthesis with age
Significance
Aging is associated with a myriad of changes at all levels of organization of an organism. However, how it affects protein synthesis, a major metabolic activity of the cell, is unknown. We discovered deregulation of protein synthesis and ribosome biogenesis machinery specifically at the translational level with age. Moreover, ribosomes were depleted in the vicinity of start codons and increased near stop codons. These findings reveal systematic, multilevel deregulation in gene expression and protein synthesis, showing how this major cellular process declines with age.
Abstract
Protein synthesis represents a major metabolic activity of the cell. However, how it is affected by aging and how this in turn impacts cell function remains largely unexplored. To address this question, herein we characterized age-related changes in both the transcriptome and translatome of mouse tissues over the entire life span. We showed that the transcriptome changes govern those in the translatome and are associated with altered expression of genes involved in inflammation, extracellular matrix, and lipid metabolism. We also identified genes that may serve as candidate biomarkers of aging. At the translational level, we uncovered sustained down-regulation of a set of 5'-terminal oligopyrimidine (5'-TOP) transcripts encoding protein synthesis and ribosome biogenesis machinery and regulated by the mTOR pathway. For many of them, ribosome occupancy dropped twofold or even more. Moreover, with age, ribosome coverage gradually decreased in the vicinity of start codons and increased near stop codons, revealing complex age-related changes in the translation process. Taken together, our results reveal systematic and multidimensional deregulation of protein synthesis, showing how this major cellular process declines with age.
https://www.pnas.org/content/117/27/15581
3. RNA-Mediated Disease Mechanisms in Neurodegenerative Disorders
Abstract
RNA is accurately entangled in virtually all pathways that maintain cellular homeostasis. To name but a few, RNA is the “messenger” between DNA encoded information and the resulting proteins. Furthermore, RNAs regulate diverse processes by forming DNA::RNA or RNA::RNA interactions. Finally, RNA itself can be the scaffold for ribonucleoprotein complexes, for example, ribosomes or cellular bodies. Consequently, disruption of any of these processes can lead to disease. This review describes known and emerging RNA-based disease mechanisms like interference with regular splicing, the anomalous appearance of RNA–protein complexes and uncommon RNA species, as well as non-canonical translation. Due to the complexity and entanglement of the above-mentioned pathways, only few drugs are available that target RNA-based disease mechanisms. However, advances in our understanding how RNA is involved in and modulates cellular homeostasis might pave the way to novel treatments.
https://www.sciencedirect.com/science/article/abs/pii/S0022283618312877
4. Alzheimer’s disease-related dysregulation of mRNA translation causes key pathological features with ageing
Alzheimer’s disease (AD) is characterised by Aß and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aß increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aß accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.
https://www.nature.com/articles/s41398-020-00882-7
5. The sigma-1 receptor is a trans-membrane protein placed in the endoplasmic reticulum (ER), which regulates the function of inositol-3-phosphate receptor, stabilizing the calcium signaling between ER and mitochondria.
The sigma-1 receptor is a trans-membrane protein placed in the endoplasmic reticulum (ER), which regulates the function of inositol-3-phosphate receptor, stabilizing the calcium signaling between ER and mitochondria. There are studies that the sigma-1 receptor is involved in the formation of many neurological and psychiatric conditions. It is assumed that the sigma-1 receptor acts as a sensor of normal calcium operation. The studies over the recent years have shown the role of the violation in calcium signaling in the pathogenesis of Alzheimer's and Huntington's diseases. In particular, changes in calcium homeostasis of the endoplasmic reticulum lead to the break of synaptic connections in the neurons. Thus, the sigma-1 receptor holds promise in application as a potential therapeutic target for the treatment of neuropathological diseases.
https://www.sciencedirect.com/science/article/pii/S2405722316300214
6.The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s
ABSTRACT
Introduction
Autophagy is a cellular catabolic mechanism that helps clear damaged cellular components and is essential for normal cellular and tissue function. The sigma-1 receptor (s-1R) is a chaperone protein involved in signal transduction, neurite outgrowth, and plasticity, improving memory, and neuroprotection. Recent evidence shows that s-1R can promote autophagy. Autophagy activation by the s-1Rs along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer’s disease. AF710B, T-817 MA, and ANAVEX2-73 are some of the s-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models.
https://www.tandfonline.com/doi/abs/10.1080/14728222.2021.1939681
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