Impact of Swiprosin-1/Efhd2 on Adult Hippocampal Neurogenesis

Swiprosin-1/Efhd2 (Efhd2) is highly expressed in the CNS during development and in the adult. EFHD2 is regulated by Ca2+ binding, stabilizes F-actin, and promotes neurite extension. Previous studies indicated a dysregulation of EFHD2 in human Alzheimer's disease brains. We hypothesized a detrimental effect of genetic ablation of Efhd2 on hippocampal integrity and specifically investigated adult hippocampal neurogenesis. Efhd2 was expressed throughout adult neuronal development and in mature neurons. We observed a severe reduction of the survival of adult newborn neurons in Efhd2 knockouts, starting at the early neuroblast stage. Spine formation and dendrite growth of newborn neurons were compromised in full Efhd2 knockouts, but not upon cell- autonomous Efhd2 deletion. Together with our finding of severe hippocampal tauopathy in Efhd2 knockout mice, these data connect Efhd2 to impaired synaptic plasticity as present in Alzheimer's disease and identify a role of Efhd2 in neuronal survival and synaptic integration in the adult hippocampus

Psychophysical Training of Young People for Homeland Defence Using Means of Physical Culture and Sports

The research prominence lies in an increasing interest of the state in patriotic education and physical training of young people for homeland defenсe. There is an urgent today to reconstruct the ethnic model of patriotic education and its component, in particular military-and-patriotic education, identify the means of physical culture and sports (physical exercise; natural, artificial and hygienic factors) and justify their use under reforms in education following the needs and demands of the individual and the society in Ukraine. The research aims to theoretically justify and experimentally verify the effectiveness of military-and-patriotic education of young people using physical culture and sports based on ethnopedagogy, following neuropedagogical criteria of their psychophysical readiness for homeland defenсe. The authors of the research offer to introduce the specialized course on martial arts of Ukraine, which refers to the worldview and mindset of Ukrainians underlying the Ukrainian military (combat) culture, as well as strengthening and enhancement of neuropsychological properties and symptom complexes of character. The control group pupils (25) were taught based on the traditional system (they acquired and improved their knowledge, abilities and skills in preliminary military training). The experimental group pupils (25) purposefully studied the specialized course on the martial arts of Ukraine. Such methods as surveys, questionnaires, tests, interviews and observations were used to conduct neuropsychological diagnostics of young people’s readiness for homeland defenсe. In EG, the number of the respondents with a high level of psychophysical readiness for homeland defenсe has increased by 10.3%; the number of the respondents with an average level of psychophysical readiness for homeland defenсe has increased only by 2.2%; the number of the respondents with a low level of psychophysical readiness for homeland defenсe has decreased by 12.5%. Modern military-and-patriotic education of young people can be considered effective if the pedagogical model of military-and patriotic education using physical culture and sports and taking into account neuropsychological and neuropedagogical factors is integrated into the modern system of national education.</p

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

Pathogenic variants in SPG11 are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs. To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11. Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Parkinson’s disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems. In this study, we investigate the impact of aSyn on microtubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCADupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments

Суспільні фінанси України

У навчальному посібнику розкрито зміст і структуру суспільних фінансів України, особливості управління ними, способи вдосконалення міжбюджетних відносин та податкової системи країни. Для студентів, які вивчають курси «Фінанси», «Державні фінанси України», «Податкова система України», а також для аспірантів, викладачів економічних спеціальностей і фахівців фінансових установ

Система місцевих платежів в Україні : теорія, історія, перспективи

У монографії обґрунтовано новий підхід до визначення системи місцевих платежів. Зокрема, висвітлено принципи їх побудови й структуру, історію формування. Розкрито особливості місцевого оподаткування України та роль загальнодержавних податків у наповненні місцевих бюджетів; сутність й особливості самооподаткування як складової частини місцевих платежів; досвід справляння місцевих платежів у зарубіжних країнах; окреслено проблеми та перспективи податкової децентралізації в Україні. Монографія призначена для студентів економічних спеціальностей, аспірантів, викладачів, науковців, усіх, кого цікавлять питання функціонування системи місцевих платежів в Україні й країнах світ

Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally, time-lapse assays performed in SPG11 patients'-derived neurons and spatacsin-silenced mouse neurons highlighted a reduction in the anterograde vesicle trafficking indicative of impaired axonal transport. By employing SPG11 patient-derived forebrain neurons and mouse cortical neurons, this study provides the first evidence that SPG11 is implicated in axonal maintenance and cargo trafficking. Understanding the cellular functions of spatacsin will allow deciphering mechanisms of motor cortex dysfunction in autosomal-recessive hereditary spastic paraplegia

Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients

IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r −/− and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.Interdisciplinary Center for Clinical Research (IZKF)http://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100003390Fritz Thyssen Stiftunghttp://dx.doi.org/10.13039/501100003042Else Kröner-Fresenius-Stiftun