Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets.
View Article and Find Full Text PDFGiven their highly polarized morphology and functional singularity, neurons require precise spatial and temporal control of protein synthesis. Alterations in protein translation have been implicated in the development and progression of a wide range of neurological and neurodegenerative disorders, including Huntington's disease (HD). In this study we examined the architecture of polysomes in their native brain context in striatal tissue from the zQ175 knock-in mouse model of HD.
View Article and Find Full Text PDFChaperonins are molecular chaperones found in all kingdoms of life, and as such they assist in the folding of other proteins. Structurally, chaperonins are cylinders composed of two back-to-back rings, each of which is an oligomer of ~60-kDa proteins. Chaperonins are found in two main conformations, one in which the cavity is open and ready to recognise and trap unfolded client proteins, and a "closed" form in which folding takes place.
View Article and Find Full Text PDFSummary: We have developed a software tool to improve the image quality in focused ion beam-scanning electron microscopy (FIB-SEM) stacks: PolishEM. Based on a Gaussian blur model, it automatically estimates and compensates for the blur affecting each individual image. It also includes correction for artifacts commonly arising in FIB-SEM (e.
View Article and Find Full Text PDFProtein homeostasis (proteostasis) is an essential pillar for correct cellular function. Impairments in proteostasis are encountered both in aging and in several human disease conditions. Molecular chaperones are important players for proteostasis; in particular, heat shock protein 70 (Hsp70) has an essential role in protein folding, disaggregation, and degradation.
View Article and Find Full Text PDFProteostasis, the controlled balance of protein synthesis, folding, assembly, trafficking and degradation, is a paramount necessity for cell homeostasis. Impaired proteostasis is a hallmark of ageing and of many human diseases. Molecular chaperones are essential for proteostasis in eukaryotic cells, and their function has traditionally been linked to protein folding, assembly and disaggregation.
View Article and Find Full Text PDFMacroautophagy is morphologically characterized by autophagosome formation. Autophagosomes are double-membraned vesicles that sequester cytoplasmic components for further degradation in the lysosome. Basal autophagy is paramount for intracellular quality control in post-mitotic cells but, surprisingly, the number of autophagosomes in post-mitotic neurons is very low, suggesting that alternative degradative structures could exist in neurons.
View Article and Find Full Text PDFProtein Eng Des Sel
January 2011
The relevance of p53 as a tumour suppressor is evident from the fact that more than 50% of the human cancers hold mutations in the gene coding for p53, and of the remaining cancers a considerable number have alterations in the p53 pathway. From its discovery 30 years ago, the importance of p53 as an essential transcription factor for tumour suppression has become clear. More recently, new and seemingly diverse roles of p53 have been discovered.
View Article and Find Full Text PDFThe endoplasmic reticulum-stress response is induced in several neurodegenerative diseases and in cellular models of Huntington's disease. However, here we report that the processing of ATF6α to its active nuclear form, one of the three branches of endoplasmic reticulum-stress activation, is impaired in both animal models and Huntington's disease patients. ATF6α has been reported to be essential for the survival of dormant tumour cells that, like neurons, are arrested in the G0-G1 phase of the cell cycle.
View Article and Find Full Text PDFp53 binds to some members of the S100 family (S100B, S100A4, S100A2, and S100A1). We previously showed that both S100B and S100A4 bind to the p53 tetramerization domain, and consequently control its oligomerization state, but only S100B binds to the C-terminal negative regulatory domain (NRD). Here, we investigate other binding partners for p53 within the S100 family (S100A6 and S100A11), and show that binding to the p53 tetramerization domain seems to be a general feature of the S100 family, while binding to the NRD is a characteristic of a subset of the family.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
March 2005
S100B protein is elevated in the brains of patients with early stages of Alzheimer's disease and Down's syndrome. S100A4 is correlated with the development of metastasis. Both proteins bind to p53 tumor suppressor.
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