Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease

Neurosteroids are steroid hormones synthesised de novo in the brain and peripheral nervous tissues. In contrast to adrenal steroid hormones that act on intracellular nuclear receptors, neurosteroids directly modulate plasma membrane ion channels and regulate intracellular signalling. This review provides an overview of the work that led to the discovery of neurosteroids, our current understanding of their intracellular biosynthetic machinery, and their roles in regulating the development and function of nervous tissue. Neurosteroids mediate signalling in the brain via multiple mechanisms. Here, we describe in detail their effects on GABA (inhibitory) and NMDA (excitatory) receptors, two signalling pathways of opposing function. Furthermore, emerging evidence points to altered neurosteroid function and signalling in neurological disease. This review focuses on neurodegenerative diseases associated with altered neurosteroid metabolism, mainly Niemann-Pick type C, multiple sclerosis and Alzheimer disease. Finally, we summarise the use of natural and synthetic neurosteroids as current and emerging therapeutics alongside their potential use as disease biomarkers

On the move, lysosomal CAX drives Ca2+ transport and motility

Acidic Ca2+ stores are important sources of Ca2+ during cell signaling but little is known about how Ca2+ enters these stores. In this issue, Melchionda et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510019) identify a Ca2+/H+ exchanger (CAX) that is required for Ca2+ uptake and cell migration in vertebrates

Investigating the prevalence of reactive online searching in the COVID-19 pandemic

Background: The ongoing coronavirus disease (COVID-19) pandemic has placed an unprecedented strain on global society, healthcare, governments and mass media. Public dissemination of government policies, medical interventions and misinformation has been remarkably rapid and largely unregulated during the COVID-19 pandemic, resulting in increased misinterpretations, miscommunication, and public panic. Being the first full-scale global pandemic of the digital age, COVID-19 has presented novel challenges pertinent to government advice, the spread of news and misinformation, and the trade-off between the accessibility of science and the premature public use of unproven medical interventions. Objective: This study aims to assess the use of internet search terms relating to COVID-19 information and misinformation during the global pandemic, identify which were most used in six affected countries, investigate any temporal trends and the likely propagators of key search terms, and determine any correlation between the per capita cases and deaths with the adoption of these search terms in each of the six countries. Methods: This study uses relative search volume data extracted from Google Trends for search terms linked to the COVID-19 pandemic alongside per capita case and mortality data extracted from the European Open Data Portal, to identify the temporal dynamics of the spread of news and misinformation during the global pandemic in six affected countries (Australia, Germany, Italy, Spain, United Kingdom, United States of America). A correlation analysis was carried out to ascertain any correlation between the temporal trends of search term use and the rise of per capita mortality and disease cases. Results: Of the selected search terms, most were searched immediately following promotion by governments, public figures or viral circulation of unfounded claims, but also relating to the publication of scientific resources, which were sometimes misinterpreted before further dissemination. Strong correlations were identified between the volume of these COVID-19-related search terms, and per capita mortality and cases. Conclusions: These findings illustrate the increased rate and volume of public consumption of novel information during a global healthcare crisis. The strong positive correlation between mortality and online searching, particularly in countries with lower COVID-19 testing rates, may demonstrate the imperative to safeguard official communications and dispel misinformation in these countries. Online news, government briefings and social media provide a powerful tool for the dissemination of important information to the public during pandemics, but their misuse, and the presentation of misrepresented medical information, should be monitored, minimised and addressed to safeguard public safety. Ultimately, governments, public health authorities and scientists have a moral imperative to safeguard the truth and maintain an accessible discourse with the public to inhibit fear

Mammalian sphingoid bases: Biophysical, physiological and pathological properties

Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules, and have been associated with numerous biological and physiological processes. In addition, they can modulate the biophysical properties of biological membranes. Several human diseases are related to pathological changes in the structure and metabolism of sphingoid bases. Yet, the mechanisms underlying their biological and pathophysiological actions remain elusive. Within this review, we aimed to summarize the current knowledge on the biochemical and biophysical properties of the most common sphingoid bases and to discuss their importance in health and disease

The crystal structure of Bacillus thuringiensis Tpp80Aa1 and its interaction with galactose-containing glycolipids

Tpp80Aa1 from Bacillus thuringiensis is a Toxin_10 family protein (Tpp) with reported action against Culex mosquitoes. Here, we demonstrate an expanded target range, showing Tpp80Aa1 is also active against the larvae of Anopheles gambiae and Aedes aegypti mosquitoes. We report the first crystal structure of Tpp80Aa1 at a resolution of 1.8 Å, which shows Tpp80Aa1 consists of two domains: an N-terminal β-trefoil domain resembling a ricin B lectin and a C-terminal putative pore-forming domain sharing structural similarity with the aerolysin family. Similar to other Tpp family members, we observe Tpp80Aa1 binds to the mosquito midgut, specifically the posterior midgut and the gastric caecum. We also identify that Tpp80Aa1 can interact with galactose-containing glycolipids and galactose, and this interaction is critical for exerting full insecticidal action against mosquito target cell lines

Hsp70 interactions with membrane lipids regulate cellular functions in health and disease

Beyond guarding the cellular proteome the major stress inducible heat shock protein Hsp70 has been shown to interact with lipids. Non-cytosolic Hsp70 stabilizes membranes during stress challenges and, in pathophysiological states, facilitates endocytosis, counteracts apoptotic mechanisms, sustains survival pathways or represents a signal that can be recognized by the immune system. Disease-coupled lipid-associated functions of Hsp70 may be targeted via distinct subcellular localizations of Hsp70 itself or its specific interacting lipids. With a special focus on interacting lipids, here we discuss localization-dependent roles of the membrane-bound Hsp70 in the context of its therapeutic potential, particularly in cancer and neurodegenerative disease

The role of glycoconjugates as receptors for insecticidal proteins

Bacillus thuringiensis (Bt) proteins are an environmentally safe and effective alternative to chemical pesticides and have been used as biopesticides, with great commercial success, for over 50 years. Global agricultural production is predicted to require a 70% increase until 2050 to provide for an increasing population. In addition to agriculture, Bt proteins are utilised to control human vectors of disease – namely mosquitoes – which account for >700,000 deaths annually. The evolution of resistance to Bt pesticial toxins threatens the progression of sustainable agriculture. Whilst Bt protein toxins are heavily utilised, the exact mechanisms behind receptor binding and toxicity are unknown. It is critical to gain a better understanding of these mechanisms in order to engineer novel toxin variants and to predict, and prevent, future resistance evolution. This review focuses on the role of carbohydrate binding in the toxicity of the most utilised group of Bt pesticidal proteins – three domain Cry (3D-Cry) toxins

Visualisation of cholesterol and ganglioside GM1 in zebrafish models of Niemann-Pick type C disease and Smith-Lemli-Opitz syndrome using light sheet microscopy

Lysosomal storage diseases are the most common cause of neurodegeneration in children. They are characterised at the cellular level by the accumulation of storage material within lysosomes. There are very limited therapeutic options, and the search for novel therapies has been hampered as few good small animal models are available. Here, we describe the use of light sheet microscopy to assess lipid storage in drug and morpholino induced zebrafish models of two diseases of cholesterol homeostasis with lysosomal dysfunction: First, Niemann–Pick type C disease (NPC), caused by mutations in the lysosomal transmembrane protein NPC1, characterised by intralysosomal accumulation of cholesterol and several other lipids. Second, Smith–Lemli–Opitz syndrome (SLOS), caused by mutations in 7-dehydrocholesterol reductase, which catalyses the last step of cholesterol biosynthesis and is characterised by intralysosomal accumulation of dietary cholesterol. This is the first description of a zebrafish SLOS model. We find that zebrafish accurately model lysosomal storage and disease-specific phenotypes in both diseases. Increased cholesterol and ganglioside GM1 were observed in sections taken from NPC model fish, and decreased cholesterol in SLOS model fish, but these are of limited value as resolution is poor, and accurate anatomical comparisons difficult. Using light sheet microscopy, we were able to observe lipid changes in much greater detail and identified an unexpected accumulation of ganglioside GM1 in SLOS model fish. Our data demonstrate, for the first time in zebrafish, the immense potential that light sheet microscopy has in aiding the resolution of studies involving lysosomal and lipid disorders

Identification of dietary alanine toxicity and trafficking dysfunction in a Drosophila model of hereditary sensory and autonomic neuropathy type 1

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is characterized by a loss of distal peripheral sensory and motorneuronal function, neuropathic pain and tissue necrosis. The most common cause of HSAN1 is due to dominant mutations in serine palmitoyl-transferase subunit 1 (SPT1). SPT catalyses the condensation of serine with palmitoyl-CoA, the initial step in sphingolipid biogenesis. Identified mutations in SPT1 are known to both reduce sphingolipid synthesis and generate catalytic promiscuity, incorporating alanine or glycine into the precursor sphingolipid to generate a deoxysphingoid base (DSB). Why either loss of function in SPT1, or generation of DSBs should generate deficits in distal sensory function remains unclear. To address these questions, we generated a Drosophila model of HSAN1. Expression of dSpt1 bearing a disease-related mutation induced morphological deficits in synapse growth at the larval neuromuscular junction consistent with a dominant-negative action. Expression of mutant dSpt1 globally was found to be mildly toxic, but was completely toxic when the diet was supplemented with alanine, when DSBs were observed in abundance. Expression of mutant dSpt1 in sensory neurons generated developmental deficits in dendritic arborization with concomitant sensory deficits. A membrane trafficking defect was observed in soma of sensory neurons expressing mutant dSpt1, consistent with endoplasmic reticulum (ER) to Golgi block. We found that we could rescue sensory function in neurons expressing mutant dSpt1 by co-expressing an effector of ER-Golgi function, Rab1 suggesting compromised ER function in HSAN1 affected dendritic neurons. Our Drosophila model identifies a novel strategy to explore the pathological mechanisms of HSAN1