Cockayne syndrome B protein: connection between repair, transcription and chromatin structure

DNA is the carrier of the genetic instructions in all living organisms. Its integrity is of vital importance for a faithful transmission of the genetic information and for the proper fimctioning of cellular processes. However, the DNA molecule is susceptible to alterations caused by both intrinsic chemical instability (e.g. deatninatioll, depurinatioll etc.) and by a wide variety of environmental and endogenous compounds. The most prominent DNAwdamaging physical agents arc ultraviolet (UV) light and ionizing radiation (X-rays and y-rays). DNA damage can disturb cellular processes and can have severe consequences on human health. Its direct effect at the cellular level is inhibition of vital processes, most notably transcription, replication and cell cycle progression. Accumulation of lesions in DNA can either lead to cell death by apoptosis or to permanent mutation

Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?

Spinal muscular atrophy (SMA) is a severe, inherited disease characterized by the progressive degeneration and death of motor neurons of the anterior horns of the spinal cord, which results in muscular atrophy and weakness of variable severity. Its early-onset form is invariably fatal in early childhood, while milder forms lead to permanent disability, physical deformities and respiratory complications. Recently, two novel revolutionary therapies, antisense oligonucleotides and gene therapy, have been approved, and might prove successful in making long-term survival of these patients likely. In this perspective, a deep understanding of the pathogenic mechanisms and of their impact on the interactions between motor neurons and other cell types within the central nervous system (CNS) is crucial. Studies using SMA animal and cellular models have taught us that the survival and functionality of motor neurons is highly dependent on a whole range of other cell types, namely glial cells, which are responsible for a variety of different functions, such as neuronal trophic support, synaptic remodeling, and immune surveillance. Thus, it emerges that SMA is likely a non-cell autonomous, multifactorial disease in which the interaction of different cell types and disease mechanisms leads to motor neurons failure and loss. This review will introduce the different glial cell types in the CNS and provide an overview of the role of glial cells in motor neuron degeneration in SMA. Furthermore, we will discuss the relevance of these findings so far and the potential impact on the success of available therapies and on the development of novel ones

Advances and Perspectives in Genetics of Congenital Thyroid Disorders

Congenital hypothyroidism (CH) is the most frequent endocrine disease in infants, affects about 1 in 3,000 newborns and is characterized by elevated levels of thyroidstimulating hormone (TSH) as a consequence of reduced thyroid function. It is also one of the most common preventable causes of cognitive and motor deficits. Prevention of CH is based on carrier identification, genetic counseling and prenatal diagnosis. In neonates a complete diagnosis of CH should include clinical examination, biochemical thyroid tests, thyroid ultrasound, radioiodine or technetium scintigraphy and perchlorate discharge test (PDT). In the last two decades, considerable progress has been made in identifying the genetic and molecular causes of CH. Knowing the prevalence of mutations in each population will facilitate greatly the molecular genetic testing. The classification based on the genetic alterations divides CH into two main categories caused: (a) by disorders of thyroid gland development (dysembriogenesis or thyroid dysgenesis group) or (b) by defects in any of the steps of thyroid hormone synthesis (dyshormonogenesis group) [1]. The dysembryogenesis or thyroid dysgenesis group, which accounts for the 80-85% of the cases, results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [1]. In only 5% of the patients, the CH is associated with mutations in genes responsible for the development or growth of thyroid cells: NKX2.1 (also known as TTF1 or T/EBP), FOXE1 (also known as TTF2 or FKHL15), paired box transcription factor 8 (PAX-8), NKX2.5, and TSHR genes [1]. Consequently, the genetic mechanisms underlying the defects in thyroid organogenesis in the majority of the cases remain to be elucidated. Epigenetic mechanisms leading to stochastic variations in the expression of multiple loci could be responsible for the sporadic characteristic of thyroid dysgenesis

Redshift determination in the X-ray band of gamma-ray bursts

If gamma-ray bursts originate in dense stellar forming regions, the interstellar material can imprint detectable absorption features on the observed X-ray spectrum. Such features can be detected by existing and planned X-ray satellites, as long as the X-ray afterglow is observed after a few minutes from the burst. If the column density of the interstellar material exceeds ~10^{23} cm^{-2} there exists the possibility to detect the K_alpha fluorescent iron line, which should be visible for more than one year, long after the X-ray afterglow continuum has faded away. Detection of these X-ray features will make possible the determination of the redshift of gamma-ray bursts even when their optical afterglow is severely dimmed by extinction.Comment: 15 pages with 5 figures. Submitted to Ap

Structural Features of Thyroglobulin Linked to Protein Trafficking

Thyroglobulin must pass endoplasmic reticulum (ER) quality control to become secreted for thyroid hormone synthesis. Defective thyroglobulin, blocked in trafficking, can cause hypothyroidism. Thyroglobulin is a large protein (~2750 residues) spanning regions I–II–III plus a C-terminal cholinesterase-like domain. The cholinesterase-like domain functions as an intramolecular chaperone for regions I–II–III, but the folding pathway leading to successful thyroglobulin trafficking remains largely unknown. Here, informed by the recent three-dimensional structure of thyroglobulin as determined by cryo-electron microscopy, we have bioengineered three novel classes of mutants yielding three entirely distinct quality control phenotypes. Specifically, upon expressing recombinant thyroglobulin, we find that first, mutations eliminating a disulfide bond enclosing a 200-amino acid loop in region I have surprisingly little impact on the ability of thyroglobulin to fold to a secretion-competent state. Next, we have identified a mutation on the surface of the cholinesterase-like domain that has no discernible effect on regional folding yet affects contact between distinct regions and thereby triggers impairment in the trafficking of full-length thyroglobulin. Finally, we have probed a conserved disulfide in the cholinesterase-like domain that interferes dramatically with local folding, and this defect then impacts on global folding, blocking the entire thyroglobulin in the ER. These data highlight variants with distinct effects on ER quality control, inhibiting domain-specific folding; folding via regional contact; neither; or both