Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders

Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disorder that targets upper and lower motor neurons and leads to fatal muscle paralysis. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for 15% of familial ALS cases, but several studies have indicated that SOD1 dysfunction may also play a pathogenic role in sporadic ALS. SOD1 induces numerous toxic effects through the pathological misfolding and aggregation of mutant SOD1 species, hence a reduction of the levels of toxic variants appears to be a promising therapeutic strategy for SOD1-related ALS. Several methods are used to modulate gene expression in vivo; these include RNA interference, antisense oligonucleotides (ASOs) and CRISPR/Cas9 technology. Areas covered: This paper examines the current approaches for gene silencing and the progress made in silencing SOD1 in vivo. It progresses to shed light on the key results and pitfalls of these studies and highlights the future challenges and new perspectives for this exciting research field. Expert opinion: Gene silencing strategies targeting SOD1 may represent effective approaches for familial and sporadic ALS-related neurodegeneration; however, the risk of off-target effects must be minimized, and effective and minimally invasive delivery strategies should be fine-tuned

The ARAUCARIA project: Grid-Based Quantitative Spectroscopic Study of Massive Blue Stars in NGC55

The quantitative study of the physical properties and chemical abundances of large samples of massive blue stars at different metallicities is a powerful tool to understand the nature and evolution of these objects. Their analysis beyond the Milky Way is challenging, nonetheless it is doable and the best way to investigate their behavior in different environments. Fulfilling this task in an objective way requires the implementation of automatic analysis techniques that can perform the analyses systematically, minimizing at the same time any possible bias. As part of the ARAUCARIA project we carry out the first quantitative spectroscopic analysis of a sample of 12 B-type supergiants in the galaxy NGC55 at 1.94 Mpc away. By applying the methodology developed in this work, we derive their stellar parameters, chemical abundances and provide a characterization of the present-day metallicity of their host galaxy. Based on the characteristics of the stellar atmosphere/line formation code FASTWIND, we designed and created a grid of models for the analysis of massive blue supergiant stars. Along with this new grid, we implemented a spectral analysis algorithm. Both tools were specially developed to perform fully consistent quantitative spectroscopic analyses of low spectral resolution of B-type supergiants in a fast and objective way. We present the main characteristics of our FASTWIND model grid and perform a number of tests to investigate the reliability of our methodology. The automatic tool is applied afterward to a sample of 12 B-type supergiant stars in NGC55, deriving the stellar parameters and abundances. The results indicate that our stars are part of a young population evolving towards a red supergiant phase. The derived chemical composition hints to an average metallicity similar to the one of the Large Magellanic Cloud, with no indication of a spatial trend across the galaxy.Comment: 19 pages, 12 figures and 9 tables. Accpeted for publication in A&

Metallicity gradients in local field star-forming galaxies: Insights on inflows, outflows, and the coevolution of gas, stars and metals

We present metallicity gradients in 49 local field star-forming galaxies. We derive gas-phase oxygen abundances using two widely adopted metallicity calibrations based on the [OIII]/Hbeta, [NII]/Halpha and [NII]/[OII] line ratios. The two derived metallicity gradients are usually in good agreement within +/-0.14 dex/R25 (R25 is the B-band iso-photoal radius), but the metallicity gradients can differ significantly when the ionisation parameters change systematically with radius. We investigate the metallicity gradients as a function of stellar mass (8<log(M*/Msun)<11) and absolute B-band luminosity (-16 > MB > -22). When the metallicity gradients are expressed in dex/kpc, we show that galaxies with lower mass and luminosity, on average, have steeper metallicity gradients. When the metallicity gradients are expressed in dex/R25, we find no correlation between the metallicity gradients, and stellar mass and luminosity. We provide a local benchmark metallicity gradient of field star-forming galaxies useful for comparison with studies at high redshifts. We investigate the origin of the local benchmark gradient using simple chemical evolution models and observed gas and stellar surface density profiles in nearby field spiral galaxies. Our models suggest that the local benchmark gradient is a direct result of the coevolution of gas and stellar disk under virtually closed-box chemical evolution when the stellar-to-gas mass ratio becomes high (>>0.3). These models imply low current mass accretion rates (<0.3xSFR), and low mass outflow rates (<3xSFR) in local field star-forming galaxies.Comment: 25 pages, 21 figures, accepted to MNRA

Noncoding RNAs in Duchenne and Becker muscular dystrophies: role in pathogenesis and future prognostic and therapeutic perspectives

Noncoding RNAs (ncRNAs), such as miRNAs and long noncoding RNAs, are key regulators of gene expression at the post-transcriptional level and represent promising therapeutic targets and biomarkers for several human diseases, including Duchenne and Becker muscular dystrophies (DMD/BMD). A role for ncRNAs in the pathogenesis of muscular dystrophies has been suggested, even if it is still incompletely understood. Here, we discuss current progress leading towards the clinical utility of ncRNAs for DMD/BMD. Long and short noncoding RNAs are differentially expressed in DMD/BMD and have a mechanism of action via targeting mRNAs. A subset of muscle-enriched miRNAs, the so-called myomiRs (miR-1, miR-133, and miR-206), are increased in the serum of patients with DMD and in dystrophin-defective animal models. Interestingly, myomiRs might be used as biomarkers, given that their levels can be corrected after dystrophin restoration in dystrophic mice. Remarkably, further evidence demonstrates that ncRNAs also play a role in dystrophin expression; thus, their modulations might represent a potential therapeutic strategy with the aim of upregulating the dystrophin protein in combination with other oligonucleotides/gene therapy approaches

Brain mitochondria, aging, and Parkinson&#8217;s disease

This paper reconsiders the role of mitochondria in aging and in Parkinson\u2019s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD

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