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  • br Epigenetic regulation of astrocyte development and functi

    2019-07-30


    Epigenetic regulation of astrocyte development and function
    Conclusion The extent of astrocyte involvement in the development and progression of neurodegenerative diseases is an active area of investigation, particularly following the development of new tools and understanding of reactive astrocyte pathways. Under basal conditions astrocytes support neurons through a variety of mechanisms, including neurotrophic support, glutamate uptake, and potassium buffering. However, reactive astrogliosis found in neurodegenerative diseases results in altered astrocyte functions to where they no longer provide support for neurons, and could potentially secrete harmful factors instead [20]. Astrocytes have garnered increased interest because they can contribute to the neuroinflammation found in neurodegenerative diseases, including AD and PD. However, the mechanisms that underlie the astrocyte-specific neuroinflammation and neurotoxicity found in these diseases are currently unknown. The field of epigenetics is still relatively new, particularly as it relates to the nervous system, and there are still significant gaps in knowledge regarding how epigenetic mechanisms can influence different cell types and responses in neurodegenerative diseases. Though much of what we know about this topic is on astrocyte development, it is clear that astrocytes in the adult UNC1999 express the various enzymes required for the different epigenetic mechanisms, including DNA methylation, histone modifications, and miRNAs, suggesting that these factors could be involved in the astrocyte response to inflammation and disease. Fig. 2 summarizes the known roles of each epigenetic mark specifically in astrocytes.
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    Introduction p21-Activated kinases (PAKs) are serine/threonine kinases that act downstream of small GTPases such as Cdc42 and Rac1. From a structural point of view, they contain a GTPase-binding domain (GBD) at the amino-terminus, also named CRIB (Cdc42- and Rac-interactive binding motif), an auto inhibitory domain (AID) and, a kinase domain at the carboxyl-terminus (Fig. 1A). In mammals, the PAK family consists of two subgroups, termed I and II. Group I PAKs (PAK1, 2 and 3) are closely related by structure and sequence, whereas PAKs of the group II (PAK4, 5 and 6) are more divergent (Fig. 1B). Overall, the kinase domain is highly conserved among all members but, the regulatory regions (AID-GBD) are structurally distinct and, consequently, the activation process differs between the two groups (Fig. 1C–D). Briefly, group I PAKs are dimers in their inactive conformation, with the AID-GBD domain interacting with the kinase domain to maintain the catalytic activity in the off state. Upon binding of the GBD with small GTPases or through other GTPase-independent mechanisms (e.g. binding to phospholipids or the exchange factor β-PIX), AID dissociates from the kinase catalytic region. Subsequently, PAKs undergo autophosphorylation and become competent to phosphorylate their substrates (reviewed in [1], [2]). In group I PAKs, the autophosphorylation residue Thr423(PAK1)/Thr402(PAK2)/Thr421(PAK3) is located within the activation loop in the kinase domain and was identified to act as a critical determinant of PAK1 activation by small GTPases and the lipid sphingosine (Fig. 1A). The Thr423Ala PAK1 mutant, which is unable to undergo autophosphorylation at this residue, showed substantially reduced kinase activity following Cdc42 activation [3]. PAK1 autophosphorylation at Thr423 was demonstrated to occur as an intermolecular event, where one active PAK1 monomer can trans-autophosphorylate the other monomer [4]. The activation mechanism of group II PAKs is different. PAK4-5-6 also contain an AID-like ‘pseudo-substrate’ at the amino-terminus that follows the GBD but, differently from group I, they are relocalized and not activated by small GTPases. Local binding partners (e.g. PS and SH motif-containing proteins) are required for the release of the catalytic domain and stimulation of group II PAK activity [5], [6]. Ser474(PAK4)/Ser602(PAK5)/Ser560(PAK6) represent the autophosphorylation-residues in the activation loop of group II PAKs and also play a pivotal role in regulating the activity and function of these kinases in cells (Fig. 1A). Group II PAKs display constitutive phosphorylation at this Ser residue in cells, with pharmacological or genetic manipulation of PAK kinase activity impacting on the phosphorylation levels of this site [7], [8]. Therefore, the degree of phosphorylation at these sites has been used as an indicator of PAKs activation in numerous studies. The marked sequence divergence among the members of group II PAKs reflects the differences in the biochemical behavior and the activation mechanisms. PAK4 is monomeric and almost inactive at basal level whereas PAK5 displays dimeric/oligomeric structures that interfere with AID binding to the catalytic domain, thus maintaining high basal kinase activity [9]. The lack of high selectivity of the individual PAKs toward substrates [10], [11], possibly due to the high degree of sequence identity among their kinase domains (Fig. 1C), suggests that the functional specificity of this class of enzymes is contingent upon the upstream stimuli that activate specific PAK isoforms and their tissue distribution and cell-type expression.