Folding, function and subcellular localization of parkin

Idiopathic Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. The specific molecular events that provoke neurodegeneration in PD are still unknown, which is an impediment to the development of neuroprotective drugs. Only recently, genes linked to hereditary forms of PD have been identified. Idiopathic and hereditary variants of PD share important pathological features, most notably the demise of dopaminergic neurons in the substantia nigra. Functional characterization of PD-associated gene products might help to understand the molecular mechanisms underlying the pathogenesis and maybe, in the future, to find preventive and curative treatments for PD. Among the mutated genes is the parkin gene (PARK2), encoding a E3 ubiquitin ligase. Mutations in the parkin gene are responsible for the majority of autosomal recessive parkinsonism. Previous work of our group revealed that misfolding and aggregation of parkin is a major mechanism of parkin inactivation, accounting for the loss-of-function phenotype of various pathogenic parkin mutants, including C-terminal deletion mutants and some missense mutants [1,2]. Remarkably, also wildtype parkin is prone to misfolding under certain cellular conditions, suggesting a more general role of parkin in the pathogenesis of PD. One aim of this thesis was to study the folding characteristics of parkin. To this end, I cloned several parkin mutants and analyzed them in cell-culture based assays to determine their folding properties. Folding analysis of these mutants revealed that pathogenic mutations can lead to aberrant parkin conformers with two distinct phenotypes. One class of mutations destabilized the native conformation of parkin, leading to its proteasomal degradation immediately after synthesis. Another class of mutants first adopted a detergent-soluble conformation, similarly to wildtype parkin. However, within hours these mutants formed relatively stable detergent-insoluble aggregates. A comparative analysis of HHARI, an E3 ubiquitin ligase with a similar modular signature, revealed that folding of parkin is specifically dependent on the integrity of the C-terminal domain, but not on the presence of a putative PDZ binding motif at the extreme C-terminus. This study provided new insight into the propensity of parkin to misfold and suggested that pathogenic mutations can induce the formation of non-native conformers at distinct steps in the folding pathway of parkin. Another focus of this thesis was the functional characterization of parkin. We and others observed that parkin protects neurons against diverse cellular insults in different model systems, indicating that it may play a role in maintaining neuronal integrity. To address the underlying mechanism, we analyzed the effect of parkin on different signaling pathways. Our results revealed that parkin has a permissive effect on NFkappaB signaling by ubiquitylating two components of the signaling cascade in a non-degradative manner. Notably, parkin lost its neuroprotective capacity in the presence of a dominant negative inhibitor of NFkappaB. In addition, we could show that parkin expression is significantly up-regulated in neurons under stress conditions, indicating that parkin is a stress-responsive protein

Improving the Socio-emotional Well-being of the Older Generation through the Implementation of Territorial Marketing

This article is based on the analysis of the possibility of using Berkman's conceptual model of mechanism of social networks influence on human health to improve the well-being of the older generation in Russia. The emphasis is put on the development of social contacts of older people through the implementation of territorial marketing. Objective and subjective indicators of well-being of older people are directly related to the characteristics and peculiarities of the territory where they live and carry out their activities (city, region, country). In this context, marketing of territory can be regarded as an activity aimed at creating and maintaining comfortable living conditions of different age groups, taking into considerations their characteristics. Special attention is paid to the social and emotional mechanisms of social support, social influence, social inclusion, social participation, interpersonal contacts and access to resources and benefits the territory of older generation. Specificity of older adults segmentation of the region (the city) is defined. The importance of active cooperation of various age groups identified in the process of territorial segmentation of the market is particularly stressed, in terms of improving the lives of older adults

Определение объема вычислительных экспериментов при решении задач оптимизационного синтеза динамических систем методом ПЛП-поиска

Даются рекомендации по выбору необходимого числа машинных экспериментов при решении конкретных задач исследования и оптимального проектирования методом ПЛП-поиска, позволяющего осуществлять глобальный квазиравномерный просмотр заданной области варьируемых параметров и применить формальные оценки из математической статистики.Recommendations about the choice of necessary number of machine experiments at the solution of specific objectives of a research and optimum design are made by method of the PLP-search allowing to carry out global quasi uniform viewing of the set area of the varied parameters and to apply formal estimates from mathematical statistics

Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity

According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk

Earthquakes, Volcanoes and God: Comparative Perspectives from Christianity and Islam

This paper asserts that both Christian and Islamic traditions of faith affect the ways in which people both try to make sense of, and respond to, disasters. This contention is supported by the results of empirical research, which demonstrates that differing Islamic and Christian perspectives on human suffering caused by disasters are neither as diverse, nor are they so intractable, as is commonly supposed. Today pastoral convergence between the two traditions may also be discerned, together with a general acceptance of the policies of both State agencies and Non-Governmental Organisations (NGOs) which are concerned with hazard relief and the propagation of policies of disaster risk reduction (DRR). Indeed some important disaster relief NGOs have emerged from Islamic and Christian faith communities and are supported by charitable donations

Cosmological Visions, Multispecies Practices, and Planetary Health in Pandemic Times

The cosmovisions of the so-called world religions are based on assumed divides between nature and culture, nonhuman and human, man and God, and these divisions have long been reproduced by the social sciences. Only recently, a radical interrelatedness has been thematized and acknowledged by certain scholars, and indeed, the current pandemic reminds us of zoonoses and the manifold relationships that humans have with other forms of life. At the same time, local or folk religions offer alternative ontologies including transgressions between humans and animals or spirits. Thus, they indicate that there is no “above” or “outside of” nature. Perhaps future multispecies practices will be shaped by a new awareness of such relatedness and symbiosis, as offered by the Planetary Health approach: a relational health concept that will prepare for future challenges by focusing on the interrelationships between human health, political, economic, and social contexts as well as the biodiversity of our planet