SummaryAggregation of misfolded proteins and the associated loss of neurons are considered a hallmark of numerous neurodegenerative diseases. Optineurin is present in protein inclusions observed in various neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob disease and Pick's disease. Optineurin deletion mutations have also been described in ALS patients. However, the role of optineurin in mechanisms of protein aggregation remains unclear. In this report, we demonstrate that optineurin recognizes various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increases protein aggregation in HeLa cells and that morpholino-silencing of the optineurin ortholog in zebrafish causes the motor axonopathy phenotype similar to a zebrafish model of ALS. A more severe phenotype is observed when optineurin is depleted in zebrafish carrying ALS mutations. Furthermore, TANK1 binding kinase 1 (TBK1) is colocalized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at serine 177 and regulates its ability to interact with autophagy modifiers. This study provides evidence for a ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates as well as additional relevance for TBK1 as an upstream regulator of the autophagic pathway.
The RhoA GTPase controls endothelial cell migration, adhesion, and barrier formation but the role of RhoB is unclear. Kovačević et al. now discover that RhoB is ubiquitinated by the CUL3–Rbx1–KCTD10 complex and that this is a prerequisite for lysosomal degradation of RhoB and the maintenance of endothelial barrier integrity.
This study suggests that IP is far more frequent than anyone could estimate. We believe that this study, covering 1906-2010 period, gives more reliable information about ophthalmological findings in IP; considering them as severe anomalies. Early detection and treatment of ophthalmological, neurological etc. findings may prevent severe consequences that IP may cause.
BackgroundSystemic inflammation, endothelial dysfunction and deficient vascularization of either uterus or myocardium are mechanistic hallmarks of early-onset preeclampsia and heart failure with preserved ejection fraction (HFpEF). HFpEF is especially prevalent in elderly women and preceded in middle age by preclinical left ventricular (LV) diastolic dysfunction.To detect if preeclampsia predisposes to HFpEF at later age, echocardiographic indices of LV function and of LV structure and biomarkers of systemic inflammation and of endothelial dysfunction were compared in middle-aged women with a history of early-onset preeclampsia or uncomplicated pregnancy.Methods and findingsMiddle-aged women with a history of early-onset preeclampsia (n = 131) or uncomplicated pregnancy (n = 56) were prospectively recruited 9 to 16 years after pregnancy.Women with a history of preeclampsia had higher body mass index (p = 0.006), blood pressure (p<0.001) and plasma levels of interleukin-6 (p = 0.005) and soluble intercellular adhesion molecule-1 (sICAM-1) (p = 0.014). They had thicker septal (p = 0.001) and posterior (p = 0.003) LV walls and worse diastolic LV function evident from reduced mean mitral annular lengthening velocity (E’mean; p = 0.007) and higher ratio of early diastolic mitral flow velocity (E) over E’mean (E/E’mean; p<0.001). Differences of sICAM-1, E’mean and E/E’mean remained significant after accounting for BMI and blood pressure.ConclusionsHistory of preeclampsia predisposes in middle age to worse LV diastolic function, which could increase the likelihood of later HFpEF development. This predisposition derives not only from persistent cardiovascular risk but may also be caused by persistent endothelial dysfunction hindering adequate vascularization in the uterus during pregnancy and in the myocardium in middle age.
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