Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis.

Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.

Phospholipid Homeostasis Regulates Dendrite Morphogenesis in Drosophila Sensory Neurons.

Disruptions in lipid homeostasis have been observed in many neurodevelopmental disorders that are associated with dendrite morphogenesis defects. However, the molecular mechanisms of how lipid homeostasis affects dendrite morphogenesis are unclear. We find that easily shocked (eas), which encodes a kinase with a critical role in phospholipid phosphatidylethanolamine (PE) synthesis, and two other enzymes in this synthesis pathway are required cell autonomously in sensory neurons for dendrite growth and stability. Furthermore, we show that the level of Sterol Regulatory Element-Binding Protein (SREBP) activity is important for dendrite development. SREBP activity increases in eas mutants, and decreasing the level of SREBP and its transcriptional targets in eas mutants largely suppresses the dendrite growth defects. Furthermore, reducing Ca2+ influx in neurons of eas mutants ameliorates the dendrite morphogenesis defects. Our study uncovers a role for EAS kinase and reveals the in vivo function of phospholipid homeostasis in dendrite morphogenesis.

[Efficiency of mequitazine in the treatment of allergic rhinitis and chronic urticaria in children. A bibliographic systematic review]. / Eficacia de la mequitazina en el tratamiento de la rinitis alérgica y urticaria crónica en niños. Revisión sistemática de la bibliografia.

BACKGROUND: Allergic rhinitis, conjunctivitis and urticaria are very frequent diseases during childhood and adult age. Second generation H1 antihistamine drugs are considered first-line treatment due to their efficacy and safety. OBJECTIVE: To assess the efficacy and adverse effects of mequitazine in the treatment of these diseases. MATERIAL AND METHODS: A bibliographic systematic review was done in order to identify the efficacy of mequitazine in the treatment of allergic rhinitis and chronic urticaria in pediatric population. This paper reviews the pharmacological features of this drug and summarizes the eleven articles that may serve as reference to review systematically in the population mentioned. Search sources were: Medline database via PubMed, Google and Cochrane Collaboration. Key words were: mequitazine, antihistamine drugs (safety, efficacy and adverse effects). Articles published in several countries with translations to English and Spanish were included. Studies were selected based on their relevance in the treatment of the diseases mentioned with the H1 antihistamine drug mequitazine. Articles were searched by title and abstract, then, the full text, from 1975 to 2006. Two researchers selected the articles for this review. RESULTS: We obtained 109 articles, from which 11 were first selected. Systematic review of articles demonstrated that mequitazine is effective and safe in the treatment of allergic rhinitis and chronic urticaria, their adverse effects are minimal and did not cause treatment cessation. Its efficacy and safety are comparable to those of other first- and second-generation antihistamine drugs. CONCLUSIONS: Mequitazine is useful for the relieve of rhinoconjunctivitis and urticaria symptoms in more than 75% of patients; however, studies done so far have included only populations with adults predominance, thus, performing clinical studies in children is justified.