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751.
Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in
various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how
the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed
these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins,
chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced
by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also
has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture
and of the amino acid homo-sequence on pathology.
Received 3 March 2006; received after revision 19 April 2006; accepted 22 May 2006 相似文献
752.
Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be
the existence of a ‘chemical barrier’ consisting in constitutively and inducibly produced antimicrobial peptides and proteins
(AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that
non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such
mediators might be ideal ‘immune stimulants’ to induce only the innate antimicrobial skin effector molecules without causing
inflammation.
Received 9 August 2005; received after revision 21 October 2005; accepted 16 November 2005 相似文献
753.
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis 总被引:21,自引:0,他引:21
Palmer CN Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJ O'Regan GM Watson RM Cecil JE Bale SJ Compton JG DiGiovanna JJ Fleckman P Lewis-Jones S Arseculeratne G Sergeant A Munro CS El Houate B McElreavey K Halkjaer LB Bisgaard H Mukhopadhyay S McLean WH 《Nature genetics》2006,38(4):441-446
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease. 相似文献
754.
Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
755.
Epigenetic asymmetry of imprinted genes in plant gametes 总被引:12,自引:0,他引:12
Gutiérrez-Marcos JF Costa LM Dal Prà M Scholten S Kranz E Perez P Dickinson HG 《Nature genetics》2006,38(8):876-878
Plant imprinted genes show parent-of-origin expression in seed endosperm, but little is known about the nature of parental imprints in gametes before fertilization. We show here that single differentially methylated regions (DMRs) correlate with allele-specific expression of two maternally expressed genes in the seed and that one DMR is differentially methylated between gametes. Thus, plants seem to have developed similar strategies as mammals to epigenetically mark imprinted genes. 相似文献
756.
Sung LY Gao S Shen H Yu H Song Y Smith SL Chang CC Inoue K Kuo L Lian J Li A Tian XC Tuck DP Weissman SM Yang X Cheng T 《Nature genetics》2006,38(11):1323-1328
Since the creation of Dolly via somatic cell nuclear transfer (SCNT), more than a dozen species of mammals have been cloned using this technology. One hypothesis for the limited success of cloning via SCNT (1%-5%) is that the clones are likely to be derived from adult stem cells. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency. 相似文献
757.
The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders. 相似文献
758.
The coagulum proteins of human semen, semenogelins I and II, are secreted in abundance by the seminal vesicles. Their function
in reproduction is poorly understood as they are rapidly degraded in ejaculated semen. However, more recent results indicate
that it is time to put the semenogelins in a broader physiological perspective that goes beyond reproduction and fertility.
Received 21 June 2006; received after revision 16 August 2006; accepted 28 September 2006 相似文献
759.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
760.