Long non-coding RNAs (lncRNA), a class of non-coding RNA molecules recently identified largely due to the efforts of FANTOM, and later GENCODE and ENCODE consortia, have been a subject of intense ...investigation in the past decade. Extensive efforts to get deeper understanding of lncRNA biology have yielded evidence of their diverse structural and regulatory roles in protecting chromosome integrity, maintaining genomic architecture, X chromosome inactivation, imprinting, transcription, translation and epigenetic regulation. Here we will briefly review the recent studies in the field of lncRNA biology focusing mostly on mammalian species and discuss their therapeutic implications.
A—Gene duplication and repurposing of pseudogenes is one of the proposed routes of lncRNA evolution. B—Mobile genetic elements (MGE) frequently initiate formation and evolution of new transcriptional units (TU) some of which become lncRNA. C—lncRNA participate in long range DNA looping essential for transcription regulation in somce loci. D—lncRNA are essential for telomere maintenance. E—lncRNA participate in X-chromosome inactivation and imprinting. F—lncRNA scaffold and regulate formation of nuclear paraspeckles, as a result also controlling the nuclear-cytoplasmic transport of mRNA. G—lncRNA are involved in formation of interchromatin granules enabling pre-mRNA splicing and maturation. H—Fine regulation of epigenetic modifications is assisted by tethering of epigenetic effectors and formation of polycomb bodies by lncRNA. I—Cytoplasmic roles of lncRNA include positive and negative regulation of mRNA stability. J—lncRNA are involved in regulation of translation and positive and negative regulation of nascent protein stability. K—lncRNA act as miRNA sponges blocking miRNA activity. Display omitted
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the ...upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.
•Expression of the Dravet syndrome gene SCN1A can be increased using oligonucleotide-based compounds (AntagoNATs) targeting a regulatory ncRNA•AntagoNAT treatment in vivo in monkeys and Dravet mice led to SCN1A upregulation and significant improvements in disease phenotype•These results outline a possible new approach for the treatment of Dravet syndrome and other disorders with similar etiology
Casein kinase Iϵ (CKIϵ), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) Keesler, G.A. et al. (2000) NeuroReport 5, 951–955. A mutation in ...CKIϵ causes a shortened circadian period in Syrian Golden hamster. We have now extended our previous studies to show that human casein kinase Iδ (hCKIδ), the closest homologue to hCKIϵ, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIδ and hCKIϵ phosphorylated and caused protein instability of human period 2 protein (hPER2). Immunohistochemical staining of rat brains demonstrates that CKIδ protein is localized in the suprachiasmatic nuclei, the central location of the master clock. These results indicate that CKIδ may play a role similar to CKIϵ, suggesting that it may also be involved in regulating circadian rhythmicity by post-translation modification of mammalian clock proteins hPER1 and 2.
In Alzheimer's disease (AD), the main histological lesion is a proteinaceous deposit, the senile plaque, which is mainly composed of a peptide called A beta. The aggregation process is thought to ...occur through enhanced concentration of A beta 40 or increased production of the more readily aggregating 42 amino acid-long A beta 42 species.
Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and immunoprecipitation procedures on synthetic and endogenous A beta produced by secreted HK293 cells. A beta and p3 production by wild-type and mutated presenilin 1-expressing cells transiently transfected with beta APP751 was monitored after metabolic labeling and immunoprecipitation procedures. Immunohistochemical analysis was performed on brains of sporadic and typical cerebrovascular amyloid angiopathy (CAA) cases.
Dot and Western blot analyses indicate that IgG-purified fractions of antisera recognize native and denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40 and A beta 42, respectively. Antibodies immunoprecipitate their respective synthetic A beta species but also A beta s and their related p3 counterparts endogenously secreted by transfected human kidney 293 cells. This allowed us to show that mutations on presenilin 1 triggered similar increased ratios of A beta 42 and its p 342 counterpart over total A beta and p3. ELISA assays allow detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500 pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and particularly labels their central dense core. In a CAA case, FCA18 and FCA3340 reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels such structures.
Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that these mutations misroute the beta APP to a compartment where gamma-secretase, but not alpha-secretase, cleavages are modified. Overall, these antibodies should prove useful for fundamental and diagnostic approaches, as suggested by their usefulness for biochemical, cell biological, and immunohistochemical techniques.
β-Amyloid peptide (A
β) is a major component of senile plaques formed in the brain of Alzheimer disease patients. We describe here a new method of quantitating A
β in biological material using liquid ...phase electrochemiluminescent system (LPECL). We used both enzyme-linked immunosorbent assay (ELISA) and LPECL methods to measure A
β and APPs
α levels in conditioned medium of
β-amyloid precursor protein (APP)-transfected CHO cells treated with known modulators of APP processing, and in CSF and plasma of guinea pigs. Our results indicate that while maintaining the accuracy and sensitivity of ELISA, LPECL is a significantly faster and less labor-intensive method for measuring of A
β and APPs
α levels in biological fluids.
According to the State Statistics a comparative analysis of total disability in the Russian Federation in 2010-2016 years was conducted, taking into account the performance of the working-age and ...over working-age population. The necessity of integration policy towards the older generation and social policy in respect of disabled persons is shown: it is advisable to make adjustments to the national strategies and programs involving the duties of authorities to protect and promote the rights of disabled people, the development of preventive, rehabilitation, medical and social trends in the interests of senior citizens are involved.
According to the State Statistics a the indicators of primary disability in 2003-2015 years in Russia were studied, taking into account the population in working and over working age first time ...recognized as disabled persons. The necessity of medical organizations improvement during the medical and social expertise of patients in different ages was shown. The characteristics of social and medical features of the primary disability were presented that should be taken into consideration in the development of social protection programs, rehabilitation of disabled people and disability prevention, especially among elderly citizens.
The principal component of Alzheimer's amyloid plaques, Abeta, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP). FE65 is a brain-enriched protein that binds to ...APP. Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes. Moreover, FE65 increases translocation of APP to the cell surface, as well as both alphaAPPs and Abeta secretion. The dramatic (4-fold) FE65-dependent increase in Abeta secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce Abeta secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.
Over the recent decade oligonucleotides have become an important new class of molecules, allowing therapeutic intervention through targets previously thought 'undruggable'. One of the new avenues ...opened up by oligonucleotide-based drugs was specific gene upregulation, which, historically, has been difficult to achieve using small-molecule drugs. This article will focus on patents covering this important development in the oligonucleotide field and highlight the different mechanisms through which the oligonucleotide-mediated gene upregulation can work, including inhibition of activity of natural antisense transcripts, interaction with promoter binding sites of noncoding regulatory RNAs, blocking of regulatory and/or miRNA binding sites in 3' UTRs, blocking splice inhibitor/enhancer sites or blocking interactions with polycomb repressive complex 2. Understanding the particular mechanism through which an oligonucleotide drug exerts its effects is highly important in drug development, as it determines the design of the drug molecule.
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