Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disruption of gamma-aminobutyric acid (GABAergic) interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences. Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an important molecular cue that may guide the movement of interneurons from their birthplace in the ganglionic eminences (GE) to their final resting place in the neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in pallial and subpallial tissues is associated with a reduction in the number of cells migrating out of GE explants. The uPAR knockout mouse provides a unique opportunity to study the effects of interneuron disruption in vivo. uPAR-/- mice have reduced HGF/SF bioactivity in the GE during the period of interneuron development and a concomitant 50% reduction in the number of GABAergic interneurons seeding frontal and parietal regions of the cerebral cortex. Behaviorally, these mice display an increased susceptibility to seizures, heightened anxiety, and diminished social interaction. This article discusses the commonalities between the functional defects seen in uPAR-/- mice and those of humans with developmental disorders, such as epilepsy, schizophrenia, and autism. It is suggested that disruption of GABAergic interneuron development may represent a common point of convergence underlying the etiologies of many of these developmental disorders.
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PMID:Disruption of interneuron development. 1620 92

Disruption of the GABAergic system has been implicated in multiple developmental disorders, including epilepsy, autism spectrum disorder and schizophrenia. The human gene encoding uPAR (PLAUR) has been shown recently to be associated with the risk of autism. The uPAR(-/-) mouse exhibits a regionally-selective reduction in GABAergic interneurons in frontal and parietal regions of the cerebral cortex as well as in the CA1 and dentate gyrus subfields of the hippocampus. Behaviorally, these mice exhibit increased sensitivity to pharmacologically-induced seizures, heightened anxiety, and atypical social behavior. Here, we explore potential alterations in GABAergic circuitry that may occur in the context of altered interneuron development. Analysis of gene expression for 13 GABA(A) receptor subunits using quantitative real-time polymerase chain reaction (PCR) indicates seven subunit mRNAs (alpha(1), alpha(2), alpha(3), beta(2), beta(3), gamma(2S) and gamma(2L)) of interest. Semi-quantitative in situ hybridization analysis focusing on these subunit mRNAs reveals a complex pattern of potential gene regulatory adaptations. The levels of alpha(2) subunit mRNAs increase in frontal cortex, CA1 and CA3, while those of alpha3 decrease in frontal cortex and CA1. In contrast, alpha(1) subunit mRNAs are unaltered in any region examined. beta(2) subunit mRNAs are increased in frontal cortex whereas beta(3) subunit mRNAs are decreased in parietal cortex. Finally, gamma(2S) subunit mRNAs are increased in parietal cortex while gamma(2L) subunit mRNAs are increased in the dentate gyrus, potentially altering the gamma(2S):gamma(2L) ratio in these two regions. For all subunits, no changes were observed in forebrain regions where GABAergic interneuron numbers are normal. We propose that disrupted differentiation of GABAergic neurons specifically in frontal and parietal cortices leads to regionally-selective alterations in local circuitry and subsequent adaptive changes in receptor subunit composition. Future electrophysiological studies will be useful in determining how alterations in network activity in the cortex and hippocampus relate to the observed behavioral phenotype.
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PMID:Genetic disruption of the autism spectrum disorder risk gene PLAUR induces GABAA receptor subunit changes. 2038 88

The urokinase receptor (uPAR) is a multifunctional glycosylphosphatidylinositol-anchored protein that regulates important processes such as gene expression, cell proliferation, adhesion, migration, invasion, and metastasis. uPAR is an essential component of the plasminogen activation cascade, a protease receptor that binds the urokinase-type plasminogen activator. uPAR is also an adhesion-modulating receptor, and a signalling receptor transmitting signals to the cell through lateral interactions with a wide array of membrane receptors. Altogether, the external ligands and membrane-bound partners of uPAR constitute a rich uPAR interactome. Recently, a new ligand of uPAR has been identified as the SRPX2 protein which is essential in language and cognitive development. SRPX2 is the second identified gene involved in language disorders. However, previous studies revealed cognitive disorders and defects in the development of the GABAergic interneurons in uPAR null mice. In addition, the expression of uPAR correlates with important human diseases such as epilepsy, autism, multiple sclerosis, Alzheimer's, AIDS dementia, cerebral malaria, and brain tumours. Therefore, uPAR has unexpectedly become a significant receptor in the central nervous system and made a few steps into philosophy. Language is indeed intimately linked to human culture. This in-depth review presents the structure and the sequences of uPAR that are essential for drug design and the generation of new inhibitors. In addition, we summarize all the inhibitors of uPAR that have been created so far. Finally, we discuss the functions of uPAR in the development, functioning, and pathology of the central nervous system.
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PMID:The urokinase receptor in the central nervous system. 2087

Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx) / Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx) / Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements.
Autism Res 2011 Feb
PMID:The autism risk genes MET and PLAUR differentially impact cortical development. 2132 67

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.
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PMID:The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system. 2171 Dec 33

Mutation in Plaur gene encoding urokinase-type plasminogen activator receptor (uPAR) results in epilepsy and autistic phenotype in mice. In humans, a single nucleotide polymorphism in PLAUR gene represents a risk for autism spectrum disorders. Importantly, the expression of uPAR is elevated in the brain after various epileptogenic insults like traumatic brain injury and status epilepticus. So far, the consequences of altered uPAR expression on brain networks are poorly known. We tested a hypothesis that uPAR regulates post-injury neuronal reorganization and consequent functional outcome, particularly epileptogenesis. Epileptogenesis was induced by intrahippocampal injection of kainate in adult male wild type (Wt) or uPAR knockout (uPAR-/-) mice, and animals were monitored with continuous (24/7) video-electroencephalogram for 30 days. The severity of status epilepticus did not differ between the genotypes. The spontaneous electrographic seizures which developed were, however, longer and their behavioral manifestations were more severe in uPAR-/- than Wt mice. The more severe epilepsy phenotype in uPAR-/- mice was associated with delayed but augmented inflammatory response and more severe neurodegeneration in the hippocampus. Also, the distribution of newly born cells in the dentate gyrus was more scattered, and the recovery of hippocampal blood vessel length from status epilepticus-induced damage was compromised in uPAR-/- mice as compared to Wt mice. Our data demonstrate that a deficiency in uPAR represents a mechanisms which results in the development of a more severe epilepsy phenotype and progressive brain pathology after status epilepticus. We suggest that uPAR represents a rational target for disease-modifying treatments after epileptogenic brain insults.
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PMID:Urokinase-type plasminogen activator receptor modulates epileptogenesis in mouse model of temporal lobe epilepsy. 2326 86

Binding of the extracellular matrix proteinase urokinase-type plasminogen activator (uPA) to its receptor, uPAR, regulates tissue remodeling during development and after injury in different organs, including the brain. Accordingly, mutations in the Plaur gene, which encodes uPAR, have been linked to language deficits, autism, and epilepsy, both in mouse and human. Whether uPAR deficiency modulates epileptogenesis and comorbidogenesis after brain injury, however, is unknown. To address this question, we induced traumatic brain injury (TBI) by controlled cortical impact (CCI) in 10 wild-type (Wt-CCI) and 16 Plaur-deficient (uPAR-CCI) mice. Sham-operated mice served as controls (10 Wt-sham, 10 uPAR-sham). During the 4-month follow-up, the mice were neurophenotyped by assessing the somatomotor performance with the composite neuroscore test, emotional learning and memory with fear conditioning to tone and context, and epileptogenesis with videoelectroencephalography monitoring and the pentylenetetrazol (PTZ) seizure susceptibility test. At the end of the testing, the mice were perfused for histology to analyze cortical and hippocampal neurodegeneration and mossy fiber sprouting. Fourteen percent (1/7) of the mice in the Wt-CCI and 0% in the uPAR-CCI groups developed spontaneous seizures (p>0.05; chi-square). Both the Wt-CCI and uPAR-CCI groups showed increased seizure susceptibility in the PTZ test (p<0.05), impaired recovery of motor function (p<0.001), and neurodegeneration in the hippocampus and cortex (p<0.05) compared with the corresponding sham-operated controls. Motor recovery and emotional learning showed a genotype effect, being more impaired in uPAR-CCI than in Wt-CCI mice (p<0.05). The findings of the present study indicate that uPAR deficiency does not increase susceptibility to epileptogenesis after CCI injury but has an unfavorable comorbidity-modifying effect after TBI.
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PMID:Epileptogenesis after traumatic brain injury in Plaur-deficient mice. 2720 24

Recently it has been found that the urokinase receptor (uPAR) and its ligands - urokinase (uPA) and SRPX2 protein play an important role in the development and functioning of the brain. There is a strong association between uPAR gene polymorphism and autism disorders in humans. Patients with autism, intractable lobe epilepsy, verbal dyspraxia and perisylvian polymicrogyria display significant changes in uPAR expression. Mice, lacking the uPAR gene develop epilepsy and demonstrate abnormal social behavior. uPA and SRPX2 protein, have been shown to be involved in pathological brain conditions such as autism, cognitive deficits and language disorders. Urokinase system that stimulates blood vessel growth as demonstrated before, also plays an important role in the regulation of the nerve growth via matrix remodeling and activation of neurotrophic and angiogenic factors. Moreover, the urokinase system also functions as a guidance system which determines the growth trajectory of the vessels' and nerves' in tissue regeneration. This review summarizes and integrates the results and recent progress in the field of uPAR and its endogenous ligands in brain development and cognitive functions.
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PMID:[PARTICIPATION OF UROKINASE RECEPTOR AND ITS ENDOGENOUS LIGANDS IN BRAIN DEVELOPMENT AND FORMATION OF COGNITIVE FUNCTIONS]. 3019 55