Te G-protein-coupled receptor signaling. RGS2 selectively accelerates the GTPase activity of Gq/11a and Gi/oa subunits. RGS2 deficiency in mice leads to hypertension and cardiac hypertrophy [119]. Endothelium-specific deletion of RGS2 caused endothelial dysfunction with impaired EDHFdependent vasodilatation [120]. In the brain, both clinical and animal models showed that lower RGS2 expression is associated with anxiety disorders [121,122]. In neurons, RGS2 was reported to regulate ionic channel function and synaptic plasticity in the hippocampus [123,124,125,126]. But how RGS2 in brain vessels interacts with neuronal sequelae in PD remains unknown. HnRNP U (heterogeneous ribonuclear protein U, also scaffold attachment facrot A, SFA) is a multi-functional nuclear matrix protein that has been implicated in multiple inflammatory pathways [127,128]. Proinflammatory toll-like receptor signaling can stimulate the translocation of hnRNP U from nuclear to cytoplasmic compartments, which then allows it to bind and stabilize mRNA of various proinflammatory Bromopyruvic acid cytokines [129]. How these inflammatory actions affect the brain vasculome in PD remains to be determined. RNF114 (RING finger protein 114, also as ZNF313, zinc finger protein 313), first identified and reported in 2003, is an ubiquitin binding protein and disease susceptibility gene for psoriasis, an immune-mediated skin disorder [130]. RNF114 is reported to regulate a positive feedback loop that enhances pathogenic doublestranded RNA induced Tetracosactrin site production of type 1 interferon by modulating RIG-1/MDA5 signaling [131]. ITSN2 (intersectins 2), a Cdc42 guanine nucleotide exchange factor (GEF), is a multidomain adaptor/scaffold protein involved in clatherin- and caveolin-mediated endocytosis, exocytosis, actin cytoskeleton rearrangement and signal transduction [132]. Several isoforms of ITSN protein can be assembled from alternative 16574785 splicing, including a brain specific isoform [133]. A role of ITSN2L in regulating endocytosis within endothelial cells has been reported [134]. PAK1 belongs to the family of p21 activated kinases. In neurons, PAK1 is known to regulate migration [135,136], spine morphogenesis and synapse formation [137], neuronal polarity [138], and hippocampal long-term potentiation [139]. Besides being a PD GWAS gene, PAK1 may also modulate or bind with other disease proteins, including Fragile X mental retardation 1 (FMR1) for Fragile X syndrome (FXS), the most commonlyinherited form of mental retardation and autism [140]; Disruptedin-Schizophrenia 1 (DISC1) for schizophrenia [141]; ALS2/Alsin for amyotrophic lateral sclerosis (ALS) [142], and Down syndrome cell adhesion molecule (DSCAM) [143]. In endothelial cells, PAK1 may regulate barrier function in different organs [144,145], and the migration of endothelial cells during angiogenesis [146]. In the context of inflammation, Pak1 is known to assist the invasion of Escherichia coli through human brain microvascular endothelial cells [147,148]. Ubiquitin C-terminal hydrolase 5 (UCHL5), is one of the proteasome 19S regulatory-particle-associated deubiquitinase. Inhibiting the activity of UCHL5 leads to cell apoptosis by altering Bax/Bcl-2 ratios and activating caspase-9 and caspase-3 [149]. Through Rpn13, UCHL5 is recruited in the 26 s proteasome complex during the deubiquitination process. it is reported to regulate the degradation of iNOS and IkappaB-alpha and participated in the process of inflammation and host defense regulation [15.Te G-protein-coupled receptor signaling. RGS2 selectively accelerates the GTPase activity of Gq/11a and Gi/oa subunits. RGS2 deficiency in mice leads to hypertension and cardiac hypertrophy [119]. Endothelium-specific deletion of RGS2 caused endothelial dysfunction with impaired EDHFdependent vasodilatation [120]. In the brain, both clinical and animal models showed that lower RGS2 expression is associated with anxiety disorders [121,122]. In neurons, RGS2 was reported to regulate ionic channel function and synaptic plasticity in the hippocampus [123,124,125,126]. But how RGS2 in brain vessels interacts with neuronal sequelae in PD remains unknown. HnRNP U (heterogeneous ribonuclear protein U, also scaffold attachment facrot A, SFA) is a multi-functional nuclear matrix protein that has been implicated in multiple inflammatory pathways [127,128]. Proinflammatory toll-like receptor signaling can stimulate the translocation of hnRNP U from nuclear to cytoplasmic compartments, which then allows it to bind and stabilize mRNA of various proinflammatory cytokines [129]. How these inflammatory actions affect the brain vasculome in PD remains to be determined. RNF114 (RING finger protein 114, also as ZNF313, zinc finger protein 313), first identified and reported in 2003, is an ubiquitin binding protein and disease susceptibility gene for psoriasis, an immune-mediated skin disorder [130]. RNF114 is reported to regulate a positive feedback loop that enhances pathogenic doublestranded RNA induced production of type 1 interferon by modulating RIG-1/MDA5 signaling [131]. ITSN2 (intersectins 2), a Cdc42 guanine nucleotide exchange factor (GEF), is a multidomain adaptor/scaffold protein involved in clatherin- and caveolin-mediated endocytosis, exocytosis, actin cytoskeleton rearrangement and signal transduction [132]. Several isoforms of ITSN protein can be assembled from alternative 16574785 splicing, including a brain specific isoform [133]. A role of ITSN2L in regulating endocytosis within endothelial cells has been reported [134]. PAK1 belongs to the family of p21 activated kinases. In neurons, PAK1 is known to regulate migration [135,136], spine morphogenesis and synapse formation [137], neuronal polarity [138], and hippocampal long-term potentiation [139]. Besides being a PD GWAS gene, PAK1 may also modulate or bind with other disease proteins, including Fragile X mental retardation 1 (FMR1) for Fragile X syndrome (FXS), the most commonlyinherited form of mental retardation and autism [140]; Disruptedin-Schizophrenia 1 (DISC1) for schizophrenia [141]; ALS2/Alsin for amyotrophic lateral sclerosis (ALS) [142], and Down syndrome cell adhesion molecule (DSCAM) [143]. In endothelial cells, PAK1 may regulate barrier function in different organs [144,145], and the migration of endothelial cells during angiogenesis [146]. In the context of inflammation, Pak1 is known to assist the invasion of Escherichia coli through human brain microvascular endothelial cells [147,148]. Ubiquitin C-terminal hydrolase 5 (UCHL5), is one of the proteasome 19S regulatory-particle-associated deubiquitinase. Inhibiting the activity of UCHL5 leads to cell apoptosis by altering Bax/Bcl-2 ratios and activating caspase-9 and caspase-3 [149]. Through Rpn13, UCHL5 is recruited in the 26 s proteasome complex during the deubiquitination process. it is reported to regulate the degradation of iNOS and IkappaB-alpha and participated in the process of inflammation and host defense regulation [15.
