KANPHOS: A Database of Kinase-Associated Neural Protein Phosphorylation in the Brain

Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The “KANPHOS” (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways.

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Endocrine Disruptors and Neurobehavioral Disorders

10.1093/acprof:oso/9780199935734.003.0006 ◽

2017 ◽

Author(s):

Heather B. Patisaul ◽

Scott M. Belcher

Keyword(s):

Endocrine Disruption ◽

Neurodegenerative Disorders ◽

Neurodevelopmental Disorders ◽

Environmental Pollutants ◽

Autism Spectrum ◽

Organophosphate Pesticides ◽

Hyperactivity Disorder ◽

Experimental Systems ◽

Neural Disorders ◽

The Brain

This chapter focuses on the role environmental pollutants are playing in the rapidly rising rate of neurodevelopmental disorders in children. The available EDC data are summarized and analyzed in relation to whether or not evidence supports a role for EDCs as contributing to neural disorders. The distinction between endocrine disruption and neurotoxicity is established by focusing on the differences between toxicants, toxins, and altered endocrine/neuroendocrine effects in organizational alterations of the brain. Evidence from experimental systems demonstrating effects of EDCs on the developing brain and the potential roles for EDCs as bad actors in rising rates of autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) are presented in detail. Additional impacts of EDCs on neurodegenerative disorders, including Parkinsons’s disease, are reviewed. The mechanisms of rotenone and paraquat neurodegeneration are compared and contrasted with the evidence and mechanisms of actions for organochlorine and organophosphate pesticides in Parkinsons’s disease.

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Reduction of cortical parvalbumin expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition

Development ◽

10.1242/dev.198390 ◽

2021 ◽

Author(s):

Till Scheuer ◽

Elena auf dem Brinke ◽

Sabine Grosser ◽

Susanne A. Wolf ◽

Daniele Mattei ◽

...

Keyword(s):

Preterm Birth ◽

Psychiatric Symptoms ◽

Autism Spectrum ◽

Morphological Properties ◽

Behavioral Deficits ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

The Brain ◽

Psychiatric Problems ◽

Behavior And Cognition

The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the mechanisms underlying are not known. In a translational hyperoxia model, exposing mice pups at age P5 to 80% oxygen for 48 hours to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin expressing interneurons until adulthood. Developmental delay of cortical myelin was observed together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor being involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning, and attention. These results elucidate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.

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PTEN and Autism With Macrocepaly

10.1093/med/9780199744312.003.0010 ◽

2013 ◽

Author(s):

Craig M. Powell

Keyword(s):

Tumor Cell ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Clinical Phenotype ◽

Model Systems ◽

Tumor Cell Lines ◽

Gene Encoding ◽

Increased Risk ◽

The Brain

Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a gene encoding an intracellular signaling molecule. PTEN was originally discovered as the gene responsible for a subset of familial hamartoma (tumor) syndromes associated with increased risk for certain cancers (Nelen et al., 1997) and as a gene often mutated in human cancers and tumor cell lines (Li et al., 1997; Steck et al., 1997). More recently, mutations in PTEN have been linked genetically to the clinical phenotype of autism or developmental delay with macrocephaly (Boccone et al., 2006; Butler et al., 2005; Buxbaum et al., 2007; Goffin, Hoefsloot, Bosgoed, Swillen, & Fryns, 2001; Herman, Butter, et al., 2007; McBride et al., 2010; Orrico et al., 2009; Stein, Elias, Saenz, Pickler, & Reynolds, 2010; Varga, Pastore, Prior, Herman, & McBride, 2009; Zori, Marsh, Graham, Marliss, & Eng, 1998). This chapter examines the role of PTEN in intracellular signaling, the link between PTEN signaling pathways and other autism-related genes and signaling pathways, the genetic relationship between PTEN and autism, model systems in which effects of Pten deletion on the brain have been studied, and promising preclinical data identifying therapeutic targets for patients with autism/macrocephaly associated with PTEN mutations.

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Visualisation of AMPA binding sites in the brain of mice lacking the adenosine A2a receptor

Neuroscience Letters ◽

10.1016/s0304-3940(00)01397-5 ◽

2000 ◽

Vol 291 (2) ◽

pp. 97-100 ◽

Cited By ~ 4

Author(s):

Broughton J Snell ◽

Jennifer L Short ◽

John Drago ◽

Catherine Ledent ◽

Andrew J Lawrence

Keyword(s):

Binding Sites ◽

Adenosine A2a Receptor ◽

A2a Receptor ◽

Adenosine A2a ◽

The Brain

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Genetics and psychophysiology of ADHD and autism

Proceedings of Science School: 2nd International Neuropsychological Summer School named after A. R. Luria “The World After the Pandemic: Challenges and Prospects for Neuroscience” ◽

10.15826/b978-5-7996-3073-7.12 ◽

2020 ◽

Author(s):

Elena I. Nikolaeva ◽

Keyword(s):

Gene Expression ◽

Attention Deficit Hyperactivity Disorder ◽

Dna Sequences ◽

Somatic Mosaicism ◽

Autism Spectrum ◽

Hyperactivity Disorder ◽

Common Causes ◽

Target Sites ◽

Copy And Paste ◽

The Brain

The paper discusses the brain mechanisms of autism and attention deficit hyperactivity disorder. It is shown that these disorders are associated with different genetic causes that create certain psychophysiological mechanisms. Nevertheless, their diagnosis is interrelated. Moreover, a child is often first diagnosed with ADHD, and then the diagnosis is changed to “autism spectrum disease”. Among the most common causes of the disease is the behavior of retrotransposons. Retrotransposons (also called transposons via intermediate RNA) are genetic elements that can amplify themselves in the genome. These DNA sequences use a “copy and paste” mechanism, whereby they are first transcribed into RNA and then converted back to identical DNA sequences via reverse transcription, and these sequences are then inserted into the genome at target sites. In humans, retro elements take up 42 % of the DNA. The conclusion is made that for the formation of an individual profile of gene expression in the neuron, the most important is the phenomenon of somatic mosaicism, due to the process of L1 retrotransposition, in addition to the classical described mechanisms of differentiation. The number of such events and their localization is significant as they are likely to contribute to the development of both autism and ADHD.

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