Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

Cardiomyopathies, neuropathies, cancer and accelerated ageing are unequivocally distinct diseases, yet they also show overlapping pathological hallmarks, including a gradual loss of genomic integrity and proteotoxic stress. Recent lines of evidence suggest that this overlap could be the result of remarkably interconnected molecular cascades between nuclear genomic instability and a loss of protein homeostasis. In this review, we discuss these complex connections, as well as their possible impact on disease. We focus in particular on the inherent ability of a wide range of genomic alterations to challenge protein homeostasis. In doing so, we provide evidence suggesting that a loss of protein homeostasis could be a far more prevalent consequence of genomic instability than generally believed. In certain cases, such as aneuploidy, a loss of protein homeostasis appears to be a crucial mechanism for pathology, which indicates that enhancing protein quality control systems could be a promising therapeutic strategy in diseases associated with genomic instability

The birth of a psychiatric orphan disorder: postpartum psychosis [Correspondence]

Feb 29 is officially marked as Rare Disease Day. Hitherto, more than 5800 rare diseases have been officially recognised, but none of these is an adult psychiatric disorder. In this leap year (2016), postpartum psychosis is included, for the first time, in the list curated by Orphanet, the reference portal for information on rare diseases

Genome instability and loss of protein homeostasis:converging paths to neurodegeneration?

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions

DNAJs:more than substrate delivery to HSPA

Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process

Interplay of the Ubiquitin Proteasome System with Nucleotide Excision Repair

Dit proefschrift kwam tot stand binnen de vakgroep Celbiologie en Genetica van de faculteit der Geneeskunde en Gezondheidswetenschappen van de Erasmus Universiteit Rotterdam. De vakgroep maakt deel uit van het Medisch Genetisch Centrum Zuid-West Nederland. Het onderzoek is financieel ondersteund door het Center for Biomedical Genetics, de Koninklijke Nederlandse Akademie van Wetenschappen en de Nederlandse Organisatie voor Wetenschappelijk Onderzoek.The genetic information stored in the DNA encodes directly or indirectly for all processes important for life. The nucleic acid order of the DNA is (via RNA) translated into proteins. The various proteins have distinct and vital functions that are important for the catalysis of the distinct processes in our cells, furthermore they function in the structures in and outside our cells as well. During the live cycle of every cell a constant challenge from both exogenous as endogenous sources potentially damages both proteins and DNA. Proteins can be easily be replaced by the synthesis of new ones. In contrast however, DNA as the carrier of information itself cannot be replaced and therefore, damage ne

Содержание и эффективность системы медико-психологической помощи в клинике детской онкологии

Проведено комплексное исследование в области детской психоонкологии, которое включало изучение психоэмоционального состояния, личностных и поведенческих особенностей онкобольных детей и их родителей, связанных с реагированием на онкологическое заболевание, семейное функционирование. Определены факторы профессионального дистресса медицинских работников и волонтеров. На основе полученных результатов разработана целостная система медико−психологической помощи и проведена оценка ее эффективности.Проведено комплексне дослідження в галузі дитячої онкології, що містило вивчення психоемоційного стану, особистісних і поведінкових особливостей онкохворих дітей та їхніх батьків, пов'язаних із реагуванням на онкологічне захворювання, сімейне функціонування. Визначено чинники професійного дистресу медичних працівників та волонтерів. На основі отриманих результатів розроблено цілісну систему медико−психологічної допомоги і проведено оцінку її ефективності.A complex investigation in the area of pediatric psychooncology including investigation of the psychoemotional state, personality and behavior peculiarities of cancer children and their parents, associated with reaction to cancer and family function, was performed. The factors of professional distress of medical staff and volunteers were determined. The obtained findings were used to work out a comprehensive system of medical psychological aid and to assess its efficacy

First-onset postpartum psychosis

Mrs. B, a 28-year-old woman with no prior psychiatric history, delivered a healthy daughter after a first, normal pregnancy. During the first two days postpartum, she was breastfeeding her daughter with notably reduced sleep. By the third day postpartum, she became convinced that her husband wanted to kill their newborn. After her mother suggested that she discontinue breastfeeding, she became extremely violent, kicking her mother in the abdomen. Over the next 4 days, the family continued to struggle as Mrs. B became progressively more impulsive, irritable, and disorganized. One week postpartum, she wa

Mother-to-infant bonding in women with a bipolar spectrum disorder

Purpose Offspring of mothers with a bipolar disorder are at high-risk for impaired developmental outcomes and psychopathology (e. g., mood, anxiety, sleep disorders) later in life. This increased risk of psychopathology is not only because of genetic vulnerability, but environmental factors may play an important role as well. The often long and debilitating mood episodes of mothers with bipolar disorder might hamper their qualities as a caregiver and may impact the child. We examined early mother-to-infant bonding 1 year postpartum in mothers with bipolar spectrum disorder as compared to mothers of the general population. The association between mother-to-infant bonding and the type of bipolar spectrum diagnosis (bipolar I, bipolar II, bipolar Not Otherwise Specified) as well as relapse within 12 months postpartum was also assessed. Methods In total, 75 pregnant women with a bipolar spectrum disorder participated in the current study. The participants were included in a longitudinal cohort study of women with bipolar spectrum disorder and were prospectively followed from pregnancy until 1 year postpartum. Mother-to-infant bonding was assessed using the Pre- and Postnatal Bonding Scale. A longitudinal population-based cohort of 1,419 pregnant women served as the control group. Multiple linear regression analyses were used to assess the association between bipolar spectrum disorder and mother-to-infant bonding scores, controlling for several confounders. Results Women with bipolar spectrum disorder perceived the bonding with their child as less positive compared to the control group. The type of bipolar spectrum disorder was not associated with poorer bonding scores. Relapse during the 1st year after delivery also did not affect bonding scores in women with bipolar spectrum disorder. Conclusions Our findings could imply that women with bipolar spectrum disorder are more vulnerable to impairments in bonding due to the nature of their psychopathology, regardless of the occurrence of postpartum relapse. Careful follow-up including monitoring of mother-to-infant bonding of pregnant women with a history of bipolar spectrum disorder should be a standard to this vulnerable group of women. In addition, regardless of severity and mood episode relapse, an intervention to improve bonding could be beneficial for all mothers with bipolar spectrum disorder and their newborns

Perinatal psychiatric episodes: a population-based study on treatment incidence and prevalence

Perinatal psychiatric episodes comprise various disorders and symptom severity, which are diagnosed and treated in multiple treatment settings. To date, no studies have quantified the incidence and prevalence of perinatal psychiatric episodes treated in primary and secondary care, which we aimed to do in the present study. We designed a descriptive prospective study and included information from Danish population registers to study first-time ever and recurrent psychiatric episodes during the perinatal period, including treatment at psychiatric facilities and general practitioners (GPs). This was done for all women who had records of one or more singleton births from 1998 until 2012. In total, we had information on 822 439 children born to 491 242 unique mothers. Results showed first-time psychiatric episodes treated at inpatient facilities were rare during pregnancy, but increased significantly shortly following childbirth (0.02 vs 0.25 per 1000 births). In comparison, first-time psychiatric episodes treated at outpatient facilities were more common, and showed little variation across pregnancy and postpartum. For every single birth resulting in postpartum episodes treated at inpatient psychiatric facilities, 2.5 births were followed by an episode treated at outpatient psychiatric facility and 12 births by GP-provided pharmacological treatment. We interpret our results the following way: treated severe and moderate psychiatric disorders have different risk patterns in relation to pregnancy and childbirth, which suggests differences in the underlying etiology. We further speculate varying treatment incidence and prevalence in pregnancy vs postpartum may indicate that the current Diagnostic and Statistical Manual of Mental Disorders-5 peripartum specifier not adequately describes at-risk periods across moderate and severe perinatal psychiatric episodes