Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a ...motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable.
Decoding ALS: from genes to mechanism Taylor, J Paul; Brown, Jr, Robert H; Cleveland, Don W
Nature (London),
2016-Nov-10, Letnik:
539, Številka:
7628
Journal Article
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Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ...ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.
Adequate zinc nutrition is essential for adequate growth, immunocompetence and neurobehavioral development, but limited information on population zinc status hinders the expansion of interventions to ...control zinc deficiency. The present analyses were conducted to: (1) estimate the country-specific prevalence of inadequate zinc intake; and (2) investigate relationships between country-specific estimated prevalence of dietary zinc inadequacy and dietary patterns and stunting prevalence.
National food balance sheet data were obtained from the Food and Agriculture Organization of the United Nations. Country-specific estimated prevalence of inadequate zinc intake were calculated based on the estimated absorbable zinc content of the national food supply, International Zinc Nutrition Consultative Group estimated physiological requirements for absorbed zinc, and demographic data obtained from United Nations estimates. Stunting data were obtained from a recent systematic analysis based on World Health Organization growth standards. An estimated 17.3% of the world's population is at risk of inadequate zinc intake. Country-specific estimated prevalence of inadequate zinc intake was negatively correlated with the total energy and zinc contents of the national food supply and the percent of zinc obtained from animal source foods, and positively correlated with the phytate: zinc molar ratio of the food supply. The estimated prevalence of inadequate zinc intake was correlated with the prevalence of stunting (low height-for-age) in children under five years of age (r = 0.48, P<0.001).
These results, which indicate that inadequate dietary zinc intake may be fairly common, particularly in Sub-Saharan Africa and South Asia, allow inter-country comparisons regarding the relative likelihood of zinc deficiency as a public health problem. Data from these analyses should be used to determine the need for direct biochemical and dietary assessments of population zinc status, as part of nationally representative nutritional surveys targeting countries estimated to be at high risk.
Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and
to ...present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.
The protein refractive index increment,
dn/dc, is an important parameter underlying the concentration determination and the biophysical characterization of proteins and protein complexes in many ...techniques. In this study, we examine the widely used assumption that most proteins have
dn/dc values in a very narrow range, and reappraise the prediction of
dn/dc of unmodified proteins based on their amino acid composition. Applying this approach in large scale to the entire set of known and predicted human proteins, we obtain, for the first time, to our knowledge, an estimate of the full distribution of protein
dn/dc values. The distribution is close to Gaussian with a mean of 0.190 ml/g (for unmodified proteins at 589 nm) and a standard deviation of 0.003 ml/g. However, small proteins <10 kDa exhibit a larger spread, and almost 3000 proteins have values deviating by more than two standard deviations from the mean. Due to the widespread availability of protein sequences and the potential for outliers, the compositional prediction should be convenient and provide greater accuracy than an average consensus value for all proteins. We discuss how this approach should be particularly valuable for certain protein classes where a high
dn/dc is coincidental to structural features, or may be functionally relevant such as in proteins of the eye.
Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the ∼10% of ALS cases that are ...dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non‐neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high‐throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin‐derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies. Ann Neurol 2013;74:309–316
Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled ...receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.
BACKGROUND: Plants require at least 14 mineral elements for their nutrition. These include the macronutrients nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg) and sulphur (S) ...and the micronutrients chlorine (Cl), boron (B), iron (Fe), manganese (Mn), copper (Cu), zinc (Zn), nickel (Ni) and molybdenum (Mo). These are generally obtained from the soil. Crop production is often limited by low phytoavailability of essential mineral elements and/or the presence of excessive concentrations of potentially toxic mineral elements, such as sodium (Na), Cl, B, Fe, Mn and aluminium (Al), in the soil solution. SCOPE: This article provides the context for a Special Issue of the Annals of Botany on 'Plant Nutrition for Sustainable Development and Global Health'. It provides an introduction to plant mineral nutrition and explains how mineral elements are taken up by roots and distributed within plants. It introduces the concept of the ionome (the elemental composition of a subcellular structure, cell, tissue or organism), and observes that the activities of key transport proteins determine species-specific, tissue and cellular ionomes. It then describes how current research is addressing the problems of mineral toxicities in agricultural soils to provide food security and the optimization of fertilizer applications for economic and environmental sustainability. It concludes with a perspective on how agriculture can produce edible crops that contribute sufficient mineral elements for adequate animal and human nutrition.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by ...clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1(+/+) stem cell line do not display the hyperexcitability phenotype. SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a ...conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.
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