Don’t Take Away My P: Phosphatases as Therapeutic Targets in Huntington’s Disease

The molecular bases that account for the preferential neurodegeneration of striatal mediumsized spiny neurons (MSNs) in Huntington’s Disease (HD) are still unknown, and different mechanisms have been proposed to contribute to the neurodegenerative process. These include mitochondrial dysfunction and metabolic impairment, transcriptional dysregulation, altered expression of trophic factors, dopamine toxicity, oxidative stress, and changes in autophagy, and huntingtin (htt) phosphorylation. In addition, excitotoxicity through the overactivation of N-methyl-D-aspartate (NMDA) receptors (NMDARs) has also been proposed to contribute to the preferential loss of these neurons (for review see Ehrnhoefer et al., 2011; Jin & Johnson, 2010; Perez-Navarro et al., 2006; Renna et al., 2010; Rosenstock et al., 2010; Weir et al., 2011). Some of these mechanisms are controlled by the attachment/removal of phosphate groups through the action of protein kinases and protein phosphatases, respectively. Therefore, alterations in their levels/activity in the presence of mutant htt (mhtt) can impact on cell survival..

Moral structuring of children during the process of obtaining informed consent in clinical and research settings

Background: Informed consent is an important factor in a child’s moral structure from which different types of doctor–patient relationships arise. Children’s autonomy is currently under discussion in terms of their decent treatment, beyond what doctors and researchers perceive. To describe the influential practices that exist among clinicians and researchers toward children with chronic diseases during the process of obtaining informed consent. Methods: This was a cross-sectional, qualitative study via a subjective and interpretivist approach. The study was performed by conducting semi-structured interviews of 21 clinicians and researchers. Data analysis was performed using the SPSS version 21® and Atlas Ti version 7.0® programs. Results: The deliberative and paternalistic models were influential practices in the physician–patient relationship. In the deliberative model, the child is expected to have a moral awareness of their care. The paternalistic model determined that submission was a way of structuring the child because he or she is considered to be a subject of extreme care. Conclusions: The differentiated objectification [educational] process recognizes the internal and external elements of the child. Informed consent proved to be an appropriate means for strengthening moral and structuring the child

Cognitive dysfunction in Huntington¿s disease: Humans, mouse models and molecular mechanisms

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder due to an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene that causes the preferential degeneration of striatal neurons. Although HD is classically considered a motor disorder, cognitive decline manifests even before the appearance of motor symptoms, and reflects the impairment of additional neuronal populations, such as cortical and hippocampal neurons, in the presence of mutant htt (mhtt). Studies on cognitive dysfunction in HD patients have focused on the cortico-striatal pathway. Here we will describe that HD patients and mouse models share many cognitive defects. Alterations in hippocampal synaptic plasticity and function found in HD mouse models highlight that changes in the functioning of the hippocampal formation contribute to cognitive dysfunction in humans. The similarity between the cognitive dysfunction in HD patients and mouse models has helped to understand better how cognitive dysfunction takes place. Moreover, it validates the use of HD mice to study the molecular mechanisms involved in HD cognitive decline. Several studies in HD mouse models indicate that altered synaptic composition/function, deficient neurotrophic support, kinase/phosphatase imbalance, and transcription dysregulation play an important role in cognitive impairment. This knowledge opens the possibility of identifying relevant therapeutic targets to fight cognitive decline in HD. The finding that in HD many mechanisms are similarly altered in hippocampal and striatal neurons suggests the possibility of a common therapeutic strategy to ameliorate both cognitive and motor dysfunction

Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease

© The Author 2015. Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Herewe aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice.We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit inHDmice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease.This work was supported by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de salud Carlos III) and by grants from Ministerio de Ciencia (MEC, MICINN, MINECO), Comunidad Autónoma de Madrid and Fundación Ramón Areces. A.M.Peer Reviewe

Practical Characterization of Cell-Electrode Electrical Models in Bio-Impedance Assays

This paper presents the fitting process followed to adjust the parameters of the electrical model associated to a cell-electrode system in Electrical Cell-substrate Impedance Spectroscopy (ECIS) technique, to the experimental results from cell-culture assays. A new parameter matching procedure is proposed, under the basis of both, mismatching between electrodes and time-evolution observed in the system response, as consequence of electrode fabrication processes and electrochemical performance of electrode-solution interface, respectively. The obtained results agree with experimental performance, and enable the evaluation of the cell number in a culture, by using the electrical measurements observed at the oscillation parameters in the test circuits employed.Ministerio de Economía y Competitividad TEC2013-46242-C3-1-

Sensing Cell-Culture Assays with Low-Cost Circuitry

An alternative approach for cell-culture end-point protocols is proposed herein. This new technique is suitable for real-time remote sensing. It is based on Electrical Cell-substrate Impedance Spectroscopy (ECIS) and employs the Oscillation-Based Test (OBT) method. Simple and straightforward circuit blocks form the basis of the proposed measurement system. Oscillation parameters – frequency and amplitude – constitute the outcome, directly correlated with the culture status. A user can remotely track the evolution of cell cultures in real time over the complete experiment through a web tool continuously displaying the acquired data. Experiments carried out with commercial electrodes and a well-established cell line (AA8) are described, obtaining the cell number in real time from growth assays. The electrodes have been electrically characterized along the design flow in order to predict the system performance and the sensitivity curves. Curves for 1-week cell growth are reported. The obtained experimental results validate the proposed OBT for cell-culture characterization. Furthermore, the proposed electrode model provides a good approximation for the cell number and the time evolution of the studied cultures.España, Feder TEC2013-46242-C3-1-

Teaching case 3-2019: Are nuclear clefts or invaginations the niche of intranuclear inclusions in FTLD-TDP?

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Age-related changes in STriatal-Enriched protein tyrosine Phosphatase levels: Regulation by BDNF

Recent results indicate that STriatal-Enriched protein tyrosine Phosphatase (STEP) levels are regulated by brain-derived neurotrophic factor (BDNF), whose expression changes during postnatal development and aging. Here, we studied STEP ontogeny in mouse brain and changes in STEP with age with emphasis on the possible regulation by BDNF. We found that STEP expression increased during the first weeks of life, reaching adult levels by 2-3 weeks of age in the striatum and cortex, and by postnatal day (P) 7 in the hippocampus. STEP protein levels were unaffected in BDNF+/- mice, but were significantly reduced in the striatum and cortex, but not in the hippocampus, of BDNF-/- mice at P7 and P14. In adult wild-type mice there were no changes in cortical and hippocampal STEP61 levels with age. Conversely, striatal STEP levels were reduced from 12 months of age, correlating with higher ubiquitination and increased BDNF content and signaling. Lower STEP levels in older mice were paralleled by increased phosphorylation of its substrates. Since altered STEP levels are involved in cellular malfunctioning events, its reduction in the striatum with increasing age should encourage future studies of how this imbalance might participate in the aging process

Relationship between the risk of falling and prescribed medication in community-dwelling elderly subjects.

Abstract Introduction: The risk of falling increases with age. A third of the population over 65 has one or more falls per year. Objetive: to know the relationship between drug prescription and falls in the elderly. Materials and Methods: a study was carried out through a community intervention in individuals ≥ 70 years of age. Results: The sample was composed of 249 participants, 160 women (64%), with a mean age of 74.47 years (SD 5.33). During the 12 months prior to the study, the mean of falls per person was 0.5 (SD 0.94), the mean of the risk factors was 2.73 (SD 1.4) and the mean of the medication prescribed was 4.2 (SD 3.0). The percentage of the reduction of falls after the study was 12%. The amount of medication prescribed correlated with the incidence of falls before and after the study, r=0.193, p=0.002 y r2=0.170, p=0.009, respectively. Prior to the study, the individuals who were prescribed beta-blockers and antidepressants, had a fall incidence of 0.74 (SD 1.14) and 1.22 (SD 1.09), respectively, however after the intervention there was no relationship between drug prescription and falls. Conclusions: the fall prevention community program was effective since it prevented the negative effects of medication on falls. An interdisciplinary community intervention reduces the global incidence of falls and the incidence of falls related to some specific medication

Social Memory and Social Patterns Alterations in the Absence of STriatal-Enriched Protein Tyrosine Phosphatase

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. Our data robustly demonstrated that STEP KO mice presented specific social memory impairment as indicated by the three-chamber sociability test, the social discrimination test, the 11-trial habituation/dishabituation social recognition test, and the novel object recognition test (NORT). This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. However, STEP KO mice showed lower exploratory activity, reduced interaction time with an intruder, less dominant behavior and higher immobility time in the tail suspension test than controls, suggesting alterations in motivation. Moreover, the extracellular levels of dopamine (DA), but not serotonin (5-HT), were increased in the dorsal striatum of STEP KO mice. Overall, our results indicate that STEP deficiency disrupts social memory and other social behaviors as well as DA homeostasis in the dorsal striatum