Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments

Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) stretch within the Huntingtin (Htt) protein. Pathogenic Htt disrupts multiple neuronal processes, including gene expression, axonal trafficking, proteasome and mitochondrial activity, and intracellular vesicle trafficking. However, the primary pathogenic mechanism and subcellular site of action for mutant Htt are still unclear. Using a Drosophila HD model, we found that pathogenic Htt expression leads to a profound overgrowth of synaptic connections that correlates directly with the levels of Htt at nerve terminals. Branches of the same nerve containing different levels of Htt show distinct phenotypes, indicating that Htt acts locally to disrupt synaptic growth. The effects of pathogenic Htt on synaptic growth arise from defective synaptic endosomal trafficking, leading to expansion of a recycling endosomal signaling compartment containing Sorting Nexin 16 and a reduction in late endosomes containing Rab11. The disruption of endosomal compartments leads to elevated BMP signaling within nerve terminals, driving excessive synaptic growth. Blocking aberrant signaling from endosomes or reducing BMP activity ameliorates the severity of HD pathology and improves viability. Pathogenic Htt is present largely in a nonaggregated form at synapses, indicating that cytosolic forms of the protein are likely to be the toxic species that disrupt endosomal signaling. Our data indicate that pathogenic Htt acts locally at nerve terminals to alter trafficking between endosomal compartments, leading to defects in synaptic structure that correlate with pathogenesis and lethality in the Drosophila HD model.National Institutes of Health (U.S.) (Grant NS40296)National Institutes of Health (U.S.) (Grant MH104536

Особенности развития экономики Казахстана: до и после кризисных явлений

The article represents the analysis of the done and forthcoming work on overcoming of structural crisis in Kazakhstan Republic. The basic stages of formation and development of economic process are characterized.Данная статья представляет собой анализ проделанной и предстоящей работы по преодолению структурного кризиса в Республике Казахстан. Охарактеризованы основные этапы формирования и развития экономического процесса

Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development

Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo. Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development.Keywords: postsynaptic scaffold, Shank, synaptic development, Wnt signalingNational Institutes of Health (U.S.) (Grant MH097680)Massachusetts Institute of Technology. Simons Center for the Social Brai

A presynaptic endosomal trafficking pathway controls synaptic growth signaling

Association of Nwk with SNX16 promotes down-regulation of synaptic growth signaling at the interface between early and recycling endosomes

The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles.

Central nerve terminals release neurotransmitter in response to a wide variety of stimuli. Since maintenance of neurotransmitter release is dependent on the continual supply of synaptic vesicles (SVs), nerve terminals possess an array of endocytosis modes to retrieve and recycle SV membrane and proteins. During mild stimulation conditions single SV retrieval modes such as clathrin-mediated endocytosis (CME) predominate. However during increased neuronal activity additional SV retrieval capacity is required, which is provided by activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mechanism during elevated neuronal activity. It is a high capacity SV retrieval mode that is immediately triggered during such stimulation conditions. This review will summarise the current knowledge regarding the molecular mechanism of ADBE, including molecules required for its triggering and subsequent steps, including SV budding from bulk endosomes. The molecular relationship between ADBE and the SV reserve pool will also be discussed. It is becoming clear that an understanding of the molecular physiology of ADBE will be of critical importance in attempts to modulate both normal and abnormal synaptic function during intense neuronal activity

Основные тенденции в области привлечения прямых иностранных инвестиций в Республике Казахстан

The author analyses the drawing of foreign investments to the Republic of Kazakhstan, and characterizes the main stages of the formation of the investment process, and also the measures to ensure the qualitative development and competitiveness of the country.Автор анализирует привлечение иностранных инвестиций в Республику Казахстан, характеризует основные этапы формирования и развития инвестиционного процесса, меры по обеспечению качественного развития и конкурентоспособности страны

Specific Features in Kazakhstan Economic Development: before and after the Crisis Phenomena

The article represents the analysis of the done and forthcoming work on overcoming of structural crisis in Kazakhstan Republic. The basic stages of formation and development of economic process are characterized

Main tendencies in drawing direct foreign investments to the republic of Kazakhstan

The author analyses the drawing of foreign investments to the Republic of Kazakhstan, and characterizes the main stages of the formation of the investment process, and also the measures to ensure the qualitative development and competitiveness of the country

Stimulation-Induced Formation of the Reserve Pool of Vesicles in Drosophila Motor Boutons

We combined electron microscopy (EM), synaptic vesicle staining by fluorescent marker FM1-43, photoconversion of the dye into an electron dense product, and electrical recordings of synaptic responses to study the distribution of reserve and recycling vesicles and its dependence on stimulation in Drosophila motor boutons. We showed that, at rest, vesicles are distributed over the periphery of the bouton, with the recycling and reserve pools being intermixed and the central core of the bouton being devoid of vesicles. Continuous high-frequency stimulation followed by a resting period mobilized the reserve vesicles into the recycling pool and, most notably, produced an increase in vesicle abundance. Recordings of synaptic activity from the temperature-sensitive endocytosis mutant shibire during continuous stimulation until complete depression provided an independent estimate of the increase in vesicle abundance on intense stimulation. EM analysis demonstrated that continuous stimulation produced an increase in the vesicle density, whereas during a subsequent resting period, vesicles filled empty areas of the bouton, spreading toward its central core. Although the observed structural potentiation did not alter basal transmitter release, it produced an increased synaptic enhancement during high-frequency stimulation. The latter effect was not observed when the boutons were potentiated using high-frequency stimulation without a subsequent resting period. We concluded therefore that the newly formed vesicles replenish the reserve pool during a resting period following intense stimulation

Genetic Analysis of Synaptotagmin C2 Domain Specificity in Regulating Spontaneous and Evoked Neurotransmitter Release

Synaptic vesicle fusion mediates communication between neurons and is triggered by rapid influx of Ca[superscript 2+]. The Ca[superscript 2+]-triggering step for fusion is regulated by the synaptic vesicle transmembrane protein Synaptotagmin 1 (Syt1). Syt1 contains two cytoplasmic C2 domains, termed C2A and C2B, which coordinate Ca[superscript 2+] binding. Although C2A and C2B share similar topology, binding of Ca[superscript 2+] ions to the C2B domain has been suggested as the only critical trigger for evoked vesicle release. If and how C2A domain function is coordinated with C2B remain unclear. In this study, we generated a panel of Syt1 chimeric constructs in Drosophila to delineate the unique and shared functions of each C2 domain in regulation of synaptic vesicle fusion. Expression of Syt 1 transgenes containing only individual C2 domains, or dual C2A-C2A or C2B-C2B chimeras, failed to restore Syt1 function in a syt1[superscript −/−] null mutant background, indicating both C2A and C2B are specifically required to support fast synchronous release. Mutations that disrupted Ca[superscript 2+] binding to both C2 domains failed to rescue evoked release, but supported synaptic vesicle docking and endocytosis, indicating that these functions of Syt1 are Ca[superscript 2+]-independent. The dual C2 domain Ca[superscript 2+]-binding mutant also enhanced spontaneous fusion while dramatically increasing evoked release when coexpressed with native Syt1. Together, these data indicate that synaptic transmission can be regulated by Syt1 multimerization and that both C2 domains of Syt1 are uniquely required for modulating Ca[superscript 2+]-independent spontaneous fusion and Ca[superscript 2+]-dependent synchronous release.National Institutes of Health (U.S.) (NIH grant NS40296