News 
Market Data 
Discover
Replies to post #208043 on Anavex Life Sciences Corp (AVXL)
09/02/19 11:21 AM
Imbalance of neuronal proteostasis is one of the pathological hallmarks of aging, and understanding its molecular defects will contribute to develop strategies to intervene age-associated disorders. Because the nervous system is highly dynamic and plastic, the manifestation of clinical features in patients arises very late, after severe damage has already occurred. Likely, it is predicted that the development of strategies to improve the quality of the aging process will substantially reduce the probability to undergo PMDs. Despite the fact that proteostasis is composed of a complex network of individual interconnected signaling pathways, recent findings suggest that the maintenance of ER physiology is a prominent molecular target to prevent age-related diseases affecting the nervous system. The involvement of ER stress in the biology of aging is complex as illustrated by most recent advances. The activity of the ER proteostasis network may not only operate as a mechanism to handle abnormal protein aggregation, but it is also proposed as an adjuster of brain function through fine-tuning synaptic function. Specific neuronal populations are highly vulnerable to perturbations to ER function possibly because their metabolic state depends on the basal activity of the UPR. Furthermore, the UPR may orchestrate repair processes of the nervous system by controlling the expression of neurotrophins such as BDNF, and the regenerative capacity of axons and stem cells pools (Castillo et al., 2015; Martinez et al., 2016b; Onate et al., 2016). Regarding inflammatory reactions, the UPR is known to have important functions in macrophages and dendritic cells by modulating the secretion of pro-inflammatory cytokines (Bettigole & Glimcher, 2015). In this context, future efforts should address the importance of the UPR to brain inflammation and the activity of astrocytes, microglia, and oligodendrocytes during aging. The fact that the UPR participates in the adjustment of energy and lipid metabolism, an additional layer of complexity, could be also explored to link the UPR with brain aging. Finally, the discovery of cell-nonautonomous UPR responses and its relation to healthspan control adds a new concept as ER stress-related signals in the brain may influence the capacity of the whole organism to adapt and cope with ER stress. All those aspects should be considered in future studies aiming to define the relative impact of ER stress on mammalian brain aging and its significance as a risk factor to develop neurodegenerative diseases.
Several novel small molecules are available to target selective UPR components and reduce ER stress levels (Table 2; Hetz et al., 2013; Maly & Papa, 2014; Gallagher & Walter, 2016; Gallagher et al., 2016; Axten, 2017), which promises possible new avenues to intervene the aging process. Importantly, some of these compounds have already been tested in preclinical models of PMDs (Table 2). However, it is important to consider possible side effects as the activity of the UPR has been linked to the physiology of many peripheral organs and the long-term administration of UPR-targeting drugs is predicted to induce liver failure, altered immune system function, pancreatic problems, among others maladies (Dufey et al., 2014). In this scenario, gene therapy is emerging as a strategy to locally reduce ER stress by delivering adaptive components of the UPR (i.e., XBP1s, BiP) specifically into the brain regions affected by distinct neurodegenerative diseases (Valenzuela et al., 2016). Overall, although the UPR is emerging as a central and evolutionarily conserved modulator of the normal process of aging, data available in mammalian systems are still correlative and remain to be functionally explored. As the UPR field has greatly evolved in the last five years in terms of generation of animal models and pharmacological tools, it is expected to witness future advances to underscore the significance of the UPR to brain aging and its relation to neurodegenerative diseases.
Sig-1R is an intracellular receptor acting as ER-chaperone (residing in the MAM) with unique pharmacological profile. It has also a unique amino acid sequence and steric structure among the receptor proteins. DMT is the endogenous ligand of Sig-1R. Oligomerization and translocation from the MAM to different biological membranes are key functional properties . The receptor has versatile cellular function and binds ligands of very diverse structure. Sig-1R is a ligand-regulated molecular chaperone which is not coupled to G-proteins. The main physiological functions (modulation of Ca2+ signaling, inhibition of voltage-dependent K+ channels, release of various neurotransmitters, immunomodulation) are known, however, the signal transduction pathways are not yet clarified.
Sig-1R is a pluripotent modulator of cellular events, regulating the inter-organelle communication and cell survival by increasing stress-response signaling. The receptor can interact with many proteins (with diverse structure and function) and can form oligomeric assemblies and heterodimers with other proteins. The existence of different oligomeric forms might provide a wide adaptability, which enables Sig-1R to interact with structurally different substrates.
Many marketed psychotropic drugs (fluvoxamine, donepezil) have affinity on Sig-1R, however, the mechanism of action is not yet clear. Receptor binding affinity and pharmacological activities frequently do not show good correlation, the molecular basis of ligand efficacy is to be discovered. Although Sig-1R agonists show neuroprotective effect in cellular and animal models, no effective registered neuroprotective drugs are on the market. Sig-1R agonists would be ideal drug candidates for translational medicine, because the known ligands have limited side effects: their modulatory action starts only under pathological conditions. A further work is required for clarifying the cellular mechanisms and molecular targets of Sig-1R. Application of Sig-1R agonists alone, very probably, will not be sufficient for the treatment of neurodegenerative diseases.
AI
