Chronic cardiac stress induces pathologic hypertrophy and fibrosis of the myocardium. The microRNA-29 (miR-29) family has been found to prevent excess collagen expression in various organs, particularly through its function in fibroblasts. Here, we show that miR-29 promotes pathologic hypertrophy of cardiac myocytes and overall cardiac dysfunction. In a mouse model of cardiac pressure overload, global genetic deletion of miR-29 or antimiR-29 infusion prevents cardiac hypertrophy and fibrosis and improves cardiac function. Targeted deletion of miR-29 in cardiac myocytes in vivo also prevents cardiac hypertrophy and fibrosis, indicating that the function of miR-29 in cardiac myocytes dominates over that in non-myocyte cell types. Mechanistically, we found cardiac myocyte miR-29 to de-repress Wnt signaling by directly targeting four pathway factors. Our data suggests that, cell- or tissue-specific antimiR-29 delivery may have therapeutic value for pathological cardiac remodeling and fibrosis.
Alzheimer's disease neuropathology is characterized by neuronal death, amyloid beta-peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimer's disease, the molecular mechanisms linking amyloid beta-peptide and paired helical filaments remain unknown. Here, we show that amyloid beta-peptide-induced nitro-oxidative damage promotes the nitrotyrosination of the glycolytic enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, nitro-triosephosphate isomerase was found to be present in brain slides from double transgenic mice overexpressing human amyloid precursor protein and presenilin 1, and in Alzheimer's disease patients. Higher levels of nitro-triosephosphate isomerase (P < 0.05) were detected, by Western blot, in immunoprecipitates from hippocampus (9 individuals) and frontal cortex (13 individuals) of Alzheimer's disease patients, compared with healthy subjects (4 and 9 individuals, respectively). Triosephosphate isomerase nitrotyrosination decreases the glycolytic flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics simulation of the nitration of tyrosines 164 and 208, close to the catalytic centre, fits with a reduced isomerase activity. Human embryonic kidney (HEK) cells overexpressing double mutant triosephosphate isomerase (Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. This finding correlates with the widespread glycation immunostaining in Alzheimer's disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large beta-sheet aggregates in vitro and in vivo, as demonstrated by turbidometric analysis and electron microscopy. Transmission electron microscopy (TEM) and atomic force microscopy studies have demonstrated that nitro-triosephosphate isomerase binds tau monomers and induces tau aggregation to form paired helical filaments, the characteristic intracellular hallmark of Alzheimer's disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimer's disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid beta-peptide-induced toxicity and tau pathology.
In BriefTau dysfunction causes neurodegeneration, and tau pathology spreading appears to occur along synaptically connected neurons.However, it is not known whether the actual presence of synapses enhances spreading.Using artificial neuronal circuits in vitro, Calafate et al. show that synaptic contacts promote spreading and that synaptic and non-synaptic mechanisms act in parallel.
Abstract PTEN-induced kinase 1 (PINK1) was first identified in cancer cells as a gene up-regulated by overexpression of the central tumour suppressor, PTEN. Loss-of-function mutations in PINK1 were subsequently discovered to cause autosomal recessive Parkinson's disease (ARPD). While much research has focused on the proposed mechanism(s) through which loss of PINKI function causes neurodegeneration, some studies indicate a potential role for this serine/threonine kinase in cancer cell biology. PINK1 is known to be a pro-survival kinase, protecting cells from several stressors, and is a key controller of mitochondrial integrity, morphology and function. This study aimed to understand the function of PINK1 in the development of cancer. Using SV40 immortalised PINK1 -/- mouse embryonic fibroblasts (MEFs), we show that loss of PINK1 results in reduced cell proliferation and foci formation, as well as decreased invasiveness. Overexpression of human PINK1 in these cells rescues these phenotypes and increases migratory capacity, indicating a tumour promoting role for PINK1. Furthermore, PINK1 loss increases autophagy and levels of reactive oxygen species, as well as enhancing mitochondrial fission. Notably, we identify PINK1 as a novel controller of cell cycle progression events which are critical to tumourigenesis. These results indicate an important function for PINK1 in cancer cell development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1117. doi:1538-7445.AM2012-1117
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