Neurodegenerative Diseases Associated with Mutations in <em>SLC25A46</em>

Neurodegenerative diseases present substantial clinical challenges. Their processes have been linked with various genetic causes, including mutations of genes encoding proteins associated with mitochondrial dynamics. Biallelic mutations in SLC25A46 have been identified as novel causes of a wide spectrum of neurological diseases with recessive inheritance, including optic atrophy, Charcot-Marie-Tooth neuropathy (CMT) type 2A neuropathy, Leigh syndrome, progressive myoclonic ataxia, and lethal congenital pontocerebellar hypoplasia. SLC25A46 (solute carrier family 25 member 46) is a membrane transit protein that is expressed in the mitochondrial outer membrane where it plays a major role in mitochondrial dynamics and cristae maintenance. This chapter presents recent findings on: (1) the clinical heterogeneity of SLC25A46-related neuropathies; (2) the SLC25A46 mutation spectrum and associated genotype-phenotype correlation; and (3) pathophysiological functions of SLC25A46 as characterized in cells and mouse models. A better understanding of the etiology of SLC25146-linked diseases will elucidate therapeutic perspectives

Specialized odorant receptors in social insects that detect cuticular hydrocarbon cues and candidate pheromones.

Eusocial insects use cuticular hydrocarbons as components of pheromones that mediate social behaviours, such as caste and nestmate recognition, and regulation of reproduction. In ants such as Harpegnathos saltator, the queen produces a pheromone which suppresses the development of workers' ovaries and if she is removed, workers can transition to a reproductive state known as gamergate. Here we functionally characterize a subfamily of odorant receptors (Ors) with a nine-exon gene structure that have undergone a massive expansion in ants and other eusocial insects. We deorphanize 22 representative members and find they can detect cuticular hydrocarbons from different ant castes, with one (HsOr263) that responds strongly to gamergate extract and a candidate queen pheromone component. After systematic testing with a diverse panel of hydrocarbons, we find that most Harpegnathos saltator Ors are narrowly tuned, suggesting that several receptors must contribute to detection and discrimination of different cuticular hydrocarbons important in mediating eusocial behaviour.Cuticular hydrocarbons (CHC) mediate the interactions between individuals in eusocial insects, but the sensory receptors for CHCs are unclear. Here the authors show that in ants such as H. saltator, the 9-exon subfamily of odorant receptors (HsOrs) responds to CHCs, and ectopic expression of HsOrs in Drosophila neurons imparts responsiveness to CHCs

Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron-sulfur clusters and for steroidogenesis. Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe-S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS). Inflammation and peripheral neuropathy are also hallmarks of this disease. In this paper, we demonstrate that FDXR mutation leads to significant optic transport defects that are likely to underlie optic atrophy, a major clinical presentation in FDXR patients, as well as a neurodegenerative loss of cells in the central nervous system (CNS). Molecular analysis indicates that FDXR mutation also leads to mitochondrial iron overload and an associated depolarization of the mitochondrial membrane, further supporting the hypothesis that FDXR mutations cause neurodegeneration by affecting FDXR\u27s critical role in iron homeostasis

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality