Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans.

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS: Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types

Feasibility and potential effectiveness of an intensive trauma-focused treatment programme for families with PTSD and mild intellectual disability

Background: Persons with mild intellectual disabilities or borderline intellectual functioning (MID-BIF; IQ 50–85) have a higher risk of being exposed to traumatic events and developing posttraumatic stress disorder (PTSD). EMDR therapy has shown to be applicable, safe and potentially effective for the treatment of PTSD in individuals with MID-BIF. However, in traumatized multi-problem families with MID-BIF and (impending) out of home placement of children, standard PTSD treatment in an outpatient setting may not be appropriate. Objective: To evaluate the feasibility and potential effectiveness of KINGS-ID, a six-week clinical trauma-focused treatment programme consisting of intensive EMDR therapy with parents and children, and parental skills training followed by two weeks of parent support at home. Method: Six families (nine parents of whom six had MID-BIF) and 10 children (all having MID-BIF) participated in the KINGS-ID programme. Seven parents and seven children had PTSD. Data were collected within a single case study design. For each family member data were collected during baseline (three measurements), treatment (seven weekly measurements), posttreatment (three measurements) and at follow-up (three measurements). Results: None of the family members dropped out. Within the first two treatment weeks all but one child and one parent no longer met PTSD symptom criteria. In both children and parents, trauma-related symptoms and daily life impairment significantly decreased following treatment and in parents a significant decrease in symptoms of general psychopathology and parental stress was found. Results were maintained at six-month follow-up. Conclusions: The findings of the current study are promising given that the treatment programme seems to offer new perspectives for traumatized multi-problem families with MID-BIF

Panel Discussion: Europe 1992

Transcript of a panel on Europe in 1992

The bidirectional relationships between online victimization and psychosocial problems in adolescents: a comparison with real-life victimization

Although peer victimization is of major concern and adolescents spend increasing amounts of time on the Internet, relatively little is known about the psychosocial antecedents and consequences of online victimization. The main aim of this study was to compare the psychosocial antecedents and consequences of online versus real-life victimization. More specifically, the bidirectional relationship between online and real-life victimization on the one hand and psychosocial problems (i.e., loneliness and social anxiety) on the other was examined. In addition, the moderating role of online aggression in the relationship between online victimization and subsequent psychosocial problems was studied. This prospective study, consisting of three annual measurements, was conducted among a sample of 831 adolescents (50.3 % girls) aged 11-15, of which most (80.2 %) had a Dutch ethnic background. The results indicate a unidirectional relationship whereby loneliness and social anxiety predict an increase in latter online victimization rather than the reverse. A bidirectional relationship was found for real-life victimization: loneliness (but not social anxiety) predicted an increase in latter real-life victimization, which in turn predicted an increase in subsequent social anxiety (but not loneliness). No moderating effects of online aggression were found. The findings of the present study suggest that negative online and in real life peer interactions have a differential meaning for, and impact on adolescents' well-being

Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations

Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including mitochondrial DNA (mtDNA). Here we examine the functions of mitochondrial fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, mitochondrial GTPases essential for fusion. Loss of the mitofusins causes severe mitochondrial dysfunction, compensatory mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of mitochondrial fusion strongly increases mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations

Cross-lagged associations between depressive symptoms and response style in adolescents

Depressive disorders are highly prevalent during adolescence and they are a major concern for individuals and society. The Response Style Theory and the Scar Theory both suggest a relationship between response styles and depressive symptoms, but the theories differ in the order of the development of depressive symptoms. Longitudinal reciprocal prospective relationships between depressive symptoms and response styles were examined in a community sample of 1343 adolescents. Additionally, response style was constructed with the traditional approach, which involves examining three response styles separately without considering the possible relations between them, and with the ratio approach, which accounts for all three response styles simultaneously. No reciprocal relationships between depressive symptoms and response style were found over time. Only longitudinal relationships between response style and depressive symptoms were significant. This study found that only depressive symptoms predicted response style, whereas the response style did not emerge as an important underlying mechanism responsible for developing and maintaining depressive symptoms in adolescents. These findings imply that prevention and intervention programs for adolescents with low depressive symptoms should not focus on adaptive and maladaptive response style strategies to decrease depressive symptoms, but should focus more on behavioral interventions

Self-control and early adolescent antisocial behavior: A longitudinal analysis

Contains fulltext : 73179.pdf (publisher's version ) (Closed access)The article discusses a three-wave longitudinal study that investigates the relationship between self-control and aggressive and delinquent behavior of early adolescent boys and girls. The sample consists of 1,012 Dutch adolescents (mean age = 12.3) in their first year of secondary education. Structural equation modeling analyses reveal that high levels of self-control consistently decrease aggressive and delinquent behavior in the subsequent 6 months follow-up intervals. Results for the total sample do not support the hypothesis that self-control is influenced by previous levels of aggression or delinquency. For boys, the partial evidence found indicates reciprocal effects of self-control and delinquency.21 p