Polymorphisms in the ACE and ADRB2 genes and risks of aging-associated phenotypes: the case of myocardial infarction.

Multiple functions of the beta2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) genes warrant studies of their associations with aging-related phenotypes. We focus on multimarker analyses and analyses of the effects of compound genotypes of two polymorphisms in the ADRB2 gene, rs1042713 and rs1042714, and 11 polymorphisms of the ACE gene, on the risk of such an aging-associated phenotype as myocardial infarction (MI). We used the data from a genotyped sample of the Framingham Heart Study Offspring (FHSO) cohort (n = 1500) followed for about 36 years with six examinations. The ADRB2 rs1042714 (C-->G) polymorphism and two moderately correlated (r(2) = 0.77) ACE polymorphisms, rs4363 (A-->G) and rs12449782 (A-->G), were significantly associated with risks of MI in this aging cohort in multimarker models. Predominantly linked ACE genotypes exhibited opposite effects on MI risks, e.g., the AA (rs12449782) genotype had a detrimental effect, whereas the predominantly linked AA (rs4363) genotype exhibited a protective effect. This trade-off occurs as a result of the opposite effects of rare compound genotypes of the ACE polymorphisms with a single dose of the AG heterozygote. This genetic trade-off is further augmented by the selective modulating effect of the rs1042714 ADRB2 polymorphism. The associations were not altered by adjustment for common MI risk factors. The results suggest that effects of single specific genetic variants of the ADRB2 and ACE genes on MI can be readily altered by gene-gene or/and gene-environmental interactions, especially in large heterogeneous samples. Multimarker genetic analyses should benefit studies of complex aging-associated phenotypes.

Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress.

Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.

Synchrony between sensory and cognitive networks is associated with subclinical variation in autistic traits

© 2015 Young, Smith, Coutlee and Huettel.Individuals with autistic spectrum disorders exhibit distinct personality traits linked to attentional, social, and affective functions, and those traits are expressed with varying levels of severity in the neurotypical and subclinical population. Variation in autistic traits has been linked to reduced functional and structural connectivity (i.e., underconnectivity, or reduced synchrony) with neural networks modulated by attentional, social, and affective functions. Yet, it remains unclear whether reduced synchrony between these neural networks contributes to autistic traits. To investigate this issue, we used functional magnetic resonance imaging to record brain activation while neurotypical participants who varied in their subclinical scores on the Autism-Spectrum Quotient (AQ) viewed alternating blocks of social and nonsocial stimuli (i.e., images of faces and of landscape scenes). We used independent component analysis (ICA) combined with a spatiotemporal regression to quantify synchrony between neural networks. Our results indicated that decreased synchrony between the executive control network (ECN) and a face-scene network (FSN) predicted higher scores on the AQ. This relationship was not explained by individual differences in head motion, preferences for faces, or personality variables related to social cognition. Our findings build on clinical reports by demonstrating that reduced synchrony between distinct neural networks contributes to a range of subclinical autistic traits.

Topoisomerase 1 (Top1)-associated Genome Instability in Yeast: Effects of Persistent Cleavage Complexes or Increased Top1 Levels

Topoisomerase 1 (Top1), a Type IB topoisomerase, functions to relieve transcription- and replication-associated torsional stress in DNA. Top1 cleaves one strand of DNA, covalently associates with the 3’ end of the nick to form a Top1-cleavage complex (Top1cc), passes the intact strand through the nick and finally re-ligates the broken strand. The chemotherapeutic drug, Camptothecin, intercalates at a Top1cc and prevents the crucial re-ligation reaction that is mediated by Top1, resulting in the conversion of a nick to a toxic double-strand break during DNA replication or the accumulation of Top1cc. This mechanism of action preferentially targets rapidly dividing tumor cells, but can also affect non-tumor cells when patients undergo treatment. Additionally, Top1 is found to be elevated in numerous tumor tissues making it an attractive target for anticancer therapies. We investigated the effects of Top1 on genome stability, effects of persistent Top1-cleavage complexes and elevated Top1 levels, in Saccharomyces cerevisiae. We found that increased levels of the Top1cc resulted in a five- to ten-fold increase in reciprocal crossovers, three- to fifteen fold increase in mutagenesis and greatly increased instability within the rDNA and CUP1 tandem arrays. Increased Top1 levels resulted in a fifteen- to twenty-two fold increase in mutagenesis and increased instability in rDNA locus. These results have important implications for understanding the effects of CPT and elevated Top1 levels as a chemotherapeutic agent.