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Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b -/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases., (© 2024. The Author(s).)

The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function., Competing Interests: Declaration of competing interest To whom it may be of interest. On behalf of all the authors, I hereby confirm that the authors of "Loss of TDP-43 Induces ALS-Related Collapse of Cellular Homeostasis" have not declared or known conflicts of interest. And to confirm that I sign the present in Lleida, at June 4th, 2024., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Spinal Muscular Atrophy (SMA) is a severe genetic neuromuscular disorder that occurs in childhood and is caused by misexpression of the survival motor neuron (SMN) protein. SMN reduction induces spinal cord motoneuron (MN) degeneration, which leads to progressive muscular atrophy and weakness. The link between SMN deficiency and the molecular mechanisms altered in SMA cells remains unclear. Autophagy, deregulation of intracellular survival pathways and ERK hyperphosphorylation may contribute to SMN-reduced MNs collapse, offering a useful strategy to develop new therapies to prevent neurodegeneration in SMA. Using SMA MN in vitro models, the effect of pharmacological inhibition of PI3K/Akt and ERK MAPK pathways on SMN and autophagy markers modulation was studied by western blot analysis and RT-qPCR. Experiments involved primary cultures of mouse SMA spinal cord MNs and differentiated SMA human MNs derived from induced pluripotent stem cells (iPSCs). Inhibition of the PI3K/Akt and the ERK MAPK pathways reduced SMN protein and mRNA levels. Importantly, mTOR phosphorylation, p62, and LC3-II autophagy markers protein level were decreased after ERK MAPK pharmacological inhibition. Furthermore, the intracellular calcium chelator BAPTA prevented ERK hyperphosphorylation in SMA cells. Our results propose a link between intracellular calcium, signaling pathways, and autophagy in SMA MNs, suggesting that ERK hyperphosphorylation may contribute to autophagy deregulation in SMN-reduced MNs., (© 2023. The Author(s).)

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the molecular mechanisms leading to cell loss in SMN-reduced MNs, we analyzed the NF-κB intracellular pathway in SMA models. NF-κB pathway activation is required for survival and regulates SMN levels in cultured MNs. Here we describe that NF-κB members, inhibitor of kappa B kinase beta (IKKβ), and RelA, were reduced in SMA mouse and human MNs. In addition, we observed that Gemin3 protein level was decreased in SMA MNs, but not in non-neuronal SMA cells. Gemin3 is a core member of the SMN complex responsible for small nuclear ribonucleoprotein biogenesis, and it regulates NF-κB activation through the mitogen-activated protein kinase TAK1. Our experiments showed that Gemin3 knockdown reduced SMN, IKKβ, and RelA protein levels, and caused significant neurite degeneration. Overexpression of SMN increased Gemin3 protein in SMA MNs, but did not prevent neurite degeneration in Gemin3 knockdown cells. These data indicated that Gemin3 reduction may contribute to cell degeneration in SMA MNs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miralles, Sansa, Beltran, Soler and Garcera.)

Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients.

Plasma in the Sun's hot corona expands into the heliosphere as a supersonic and highly magnetized solar wind. This paper provides an overview of our current understanding of how the corona is heated and how the solar wind is accelerated. Recent models of magnetohydrodynamic turbulence have progressed to the point of successfully predicting many observed properties of this complex, multi-scale system. However, it is not clear whether the heating in open-field regions comes mainly from the dissipation of turbulent fluctuations that are launched from the solar surface, or whether the chaotic 'magnetic carpet' in the low corona energizes the system via magnetic reconnection. To help pin down the physics, we also review some key observational results from ultraviolet spectroscopy of the collisionless outer corona., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

As the interface between the Sun's photosphere and corona, the chromosphere and transition region play a key role in the formation and acceleration of the solar wind. Observations from the Interface Region Imaging Spectrograph reveal the prevalence of intermittent small-scale jets with speeds of 80 to 250 kilometers per second from the narrow bright network lanes of this interface region. These jets have lifetimes of 20 to 80 seconds and widths of ≤300 kilometers. They originate from small-scale bright regions, often preceded by footpoint brightenings and accompanied by transverse waves with amplitudes of ~20 kilometers per second. Many jets reach temperatures of at least ~10(5) kelvin and constitute an important element of the transition region structures. They are likely an intermittent but persistent source of mass and energy for the solar wind., (Copyright © 2014, American Association for the Advancement of Science.)

We present a comprehensive study of the physical and chemical conditions along the TMC-1 ridge. Temperatures were estimated from observations of CH3CCH, NH3, and CO. Densities were obtained from a multitransition study of HC3N. The values of the density and temperature allow column densities for 13 molecular species to be estimated from statistical equilibrium calculations, using observations of rarer isotopomers where possible, to minimize opacity effects. The most striking abundance variations relative to HCO+ along the ridge were seen for HC3N, CH3CCH, and SO, while smaller variations were seen in CS, C2H, and HCN. On the other hand, the NH3, HNC, and N2H+ abundances relative to HCO+ were determined to be constant, indicating that the so-called NH3 peak in TMC-1 is probably a peak in the ammonia column density rather than a relative abundance peak. In contrast, the well-studied cyanopolyyne peak is most likely due to an enhancement in the abundance of long-chain carbon species. Comparisons of the derived abundances to the results of time-dependent chemical models show good overall agreement for chemical timescales around 10(5) yr. We find that the observed abundance gradients can be explained either by a small variation in the chemical timescale from 1.2 x 10(5) to 1.8 x 10(5) yr or by a factor of 2 change in the density along the ridge. Alternatively, a variation in the C/O ratio from 0.4 to 0.5 along the ridge produces an abundance gradient similar to that observed.

The availability of multidisciplinary care for rheumatoid arthritis is still limited. The Raoul Dufy Program offered by the Saint-Antoine Teaching Hospital in Paris provides one-on-one personalized care in a day hospital setting as an adjunct to conventional medical follow-up. Listening and providing information and education are major objectives of the nurse, rheumatologist and physical therapist participating in the program. The team also includes a social worker, a surgeon, a dietician, a podiatrist and a psychologist, who intervene as needed. Seventy patients attended the program between December 1993 and September 1995 and were asked to complete a baseline and a three-month questionnaire designed to evaluate the effects of the program in terms of new therapeutic interventions, patient knowledge and quality of life. The patient knowledge score increased significantly (P < 0.0001). Many therapeutic interventions were initiated after program attendance, especially in the fields of podiatry, psychology and physical therapy. However, the quality of life score failed to improve. These results and the substantial patient demand for appointments are encouraging. Further work is needed on the methodology of multidisciplinary care evaluation. Coping strategy evaluation tools may allow to identify some of the specific benefits provided by the multidisciplinary approach.