Phosphatidylserine Increases IKBKAP Levels in Familial Dysautonomia Cells

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from abnormal development and progressive degeneration of the sensory and autonomic nervous system. The mutation observed in almost all FD patients is a point mutation at position 6 of intron 20 of the IKBKAP gene; this gene encodes the IκB kinase complex-associated protein (IKAP). The mutation results in a tissue-specific splicing defect: Exon 20 is skipped, leading to reduced IKAP protein expression. Here we show that phosphatidylserine (PS), an FDA-approved food supplement, increased IKAP mRNA levels in cells derived from FD patients. Long-term treatment with PS led to a significant increase in IKAP protein levels in these cells. A conjugate of PS and an omega-3 fatty acid also increased IKAP mRNA levels. Furthermore, PS treatment released FD cells from cell cycle arrest and up-regulated a significant number of genes involved in cell cycle regulation. Our results suggest that PS has potential for use as a therapeutic agent for FD. Understanding its mechanism of action may reveal the mechanism underlying the FD disease

Sugar and metabolic health: Is there still a debate?

Purpose of review There is considerable political and public awareness of new recommendations to reduce sugars and sugar-sweetened beverages in our diets. It is therefore timely to review the most recent changes in guidelines, with a focus on evidence for metabolic health, recent research in the area and gaps in our knowledge. Recent findings Sufficient evidence links a high intake of sugar to dental caries and obesity, and high intakes of sugar-sweetened beverages in particular to increased risk of type 2 diabetes. This has led to the updating of dietary recommendations related to added sugars in the diet. The effects of specific sugars at usual intakes as part of an isoenergetic diet are less clear. The glycaemic response to food is complex and mediated by many factors, but sugar intake is not necessarily the major component. Summary There are many challenges faced by healthcare professionals and government bodies in order to improve the health of individuals and nations through evidence-based diets. Sufficiently powered long-term mechanistic studies are still required to provide evidence for the effects of reducing dietary sugars on metabolic health. However, there are many challenges for research scientists in the implementation of these studies

The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel

TRPML1 ( mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential ( TRP) proteins(1-3). Mutations in the human TRPML1 gene cause mucolipidosis type IV disease ( ML4)4,5.ML4 patients have motor impairment, mental retardation, retinal degeneration and iron- deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration(6,7), it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+- bound transferrin receptors(6), or after lysosomal degradation of ferritin - iron complexes and autophagic ingestion of iron-containing macromolecules(6,8), is the chief source of cellular iron. The divalent metal transporter protein DMT1 ( also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors(6,9). Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+ transport protein(9). By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch- clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1(-/-) ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe2+ levels and an accumulation of lipofuscin- like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transportmay contribute to both haematological and degenerative symptoms of ML4 patients.Department of Molecular, Cellular ; Developmental Biology and Biological Science Scholar Program ; University of MichiganThis work is supported by start-up funds to H. X. from the Department of Molecular, Cellular, and Developmental Biology and Biological Science Scholar Program, University of Michigan. We thank U. Brunk, M. Saito, R. Hume, C. Duan, M. Akaaboune, J. Kuwada, S. Low, S. Punthambaker and S. Dellal for assistance, and D. Clapham, N. Andrews, L. DeFelice, L. Yue, D. Ren, C. Jiang and S. Xu for comments on an earlier version of the manuscript. We also thank K. Kiselyov for sharing his unpublished results on lysosomal iron staining of ML4 cells. We appreciate the encouragement and helpful comments from other members of the Xu laboratory.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62672/1/nature07311.pd

Environment dominates over host genetics in shaping human gut microbiota

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds