Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.
Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing ␣-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, ␥-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of ␣-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of nonapoptotic cells but only in 10% of apoptotic cells. Additionally, ␣-synuclein-induced apoptosis was not coupled with increased prevalence of aggresomebearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of ␣-synuclein and synphilin-1.
Autologous BM-MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185-2197).
Stem cells are undifferentiated cells, which have the important properties of self-renewal and differentiation. Adipose-derived stem cells (ADSC) have relative advantages in accessibility and abundance compared to other kinds of stem cells. Regeneration therapy using ADSC has received attention in the treatment of various dermatologic diseases. In previous studies, ADSC were shown to have antioxidant, whitening and wound-healing effects in the skin through secretion of growth factors and by activating fibroblasts. In this study, we investigated whether ADSC could be used as an anti-ageing therapy, especially by dermal collagen synthesis and angiogenesis. Subcutaneous injection of ADSC significantly increased collagen synthesis in hairless mice, and dermal thickness, collagen density and fibroblast number also increased. In addition, procollagen type I protein and mRNA expression increased, which accounts for the increased dermal collagen density. Angiogenesis, which was visualized by CD31 and NG2 immunofluorescence stains, also increased in ADSC-treated skin. Our results suggest that ADSC therapy may be useful in ageing skin. Its effects are mainly mediated by stimulating collagen synthesis in dermal fibroblasts and increasing angiogenesis.
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