CAG repeat expansion in the Huntington's disease gene shapes linear and circular RNAs biogenesis.

Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD).

Increased Levels of the Parkinson's Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status.

Autosomal dominant mutations in the gene encoding α-synuclein () were the first to be linked with hereditary Parkinson's disease (PD). Duplication and triplication of has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. By overexpressing human α-synuclein in the neuronal system of , we functionally validated the ability of , an ortholog of the GWAS identified risk gene, Inositol-trisphosphate 3-kinase B (), to modulate α-synuclein toxicity in vivo.

CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing.

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.

Induced Pluripotent Stem Cell (iPSC) Lines from a Family with Resistant Epileptic Encephalopathy Caused by Compound Heterozygous Mutations in Gene.

Mutations in the SZT2 gene have been associated with developmental and epileptic encephalopathy-18, a rare severe autosomal recessive neurologic disorder, characterized by psychomotor impairment/intellectual disability, dysmorphic facial features and early onset of refractory seizures. Here we report the generation of the first induced pluripotent stem cell (iPSC) lines from a patient with treatment-resistant epilepsy, carrying compound heterozygous mutations in SZT2 (Mut1: c.498G>T and Mut2: c.

Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation.

SINEUP is a new class of long non-coding RNAs (lncRNAs) which contain an inverted Short Interspersed Nuclear Element (SINE) B2 element (invSINEB2) necessary to specifically upregulate target gene translation. Originally identified in the mouse AS-Uchl1 (antisense Ubiquitin carboxyl-terminal esterase L1) locus, natural SINEUP molecules are oriented head to head to their sense protein coding, target gene (Uchl1, in this example). Peculiarly, SINEUP is able to augment, in a specific and controlled way, the expression of the target protein, with no alteration of target mRNA levels.

Natural SINEUP RNAs in Autism Spectrum Disorders: Dysregulation in a Neuronal Suppression Model Leads to RAB11B Protein Increase.

represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region.

The Unexpected Tuners: Are LncRNAs Regulating Host Translation during Infections?

Pathogenic bacteria produce powerful virulent factors, such as pore-forming toxins, that promote their survival and cause serious damage to the host. Host cells reply to membrane stresses and ionic imbalance by modifying gene expression at the epigenetic, transcriptional and translational level, to recover from the toxin attack. The fact that the majority of the human transcriptome encodes for non-coding RNAs (ncRNAs) raises the question: do host cells deploy non-coding transcripts to rapidly control the most energy-consuming process in cells-i.

Epigenetics of Huntington's Disease.

Huntington's disease (HD) is a genetic, fatal autosomal dominant neurodegenerative disorder typically occurring in midlife with symptoms ranging from chorea, to dementia, to personality disturbances (Philos Trans R Soc Lond Ser B Biol Sci 354:957-961, 1999). HD is inherited in a dominant fashion, and the underlying mutation in all cases is a CAG trinucleotide repeat expansion within exon 1 of the HD gene (Cell 72:971-983, 1993). The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities.

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype.

Arnica montana (Arnica m.) is used for its purported anti-inflammatory and tissue healing actions after trauma, bruises, or tissue injuries, but its cellular and molecular mechanisms are largely unknown. This work tested Arnica m.

Transcriptomic Profiling Discloses Molecular and Cellular Events Related to Neuronal Differentiation in SH-SY5Y Neuroblastoma Cells.

Human SH-SY5Y neuroblastoma cells are widely utilized in in vitro studies to dissect out pathogenetic mechanisms of neurodegenerative disorders. These cells are considered as neuronal precursors and differentiate into more mature neuronal phenotypes under selected growth conditions. In this study, in order to decipher the pathways and cellular processes underlying neuroblastoma cell differentiation in vitro, we performed systematic transcriptomic (RNA-seq) and bioinformatic analysis of SH-SY5Y cells differentiated according to a two-step paradigm: retinoic acid treatment followed by enriched neurobasal medium.

Characterization of 17 strains belonging to the Mycobacterium simiae complex and description of Mycobacterium paraense sp. nov.

Fourteen mycobacterial strains isolated from pulmonary samples of independent patients in the state of Pará (Brazil), and three strains isolated in Italy, were characterized using a polyphasic approach. Thorough genetic investigation, including whole-genome sequencing, demonstrated that the strains belong to the M. simiae complex, being most closely related to Mycobacterium interjectum.

The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice.

The mechanotransduction process in hair cells in the inner ear is associated with the influx of calcium from the endolymph. Calcium is exported back to the endolymph via the splice variant w/a of the PMCA2 of the stereocilia membrane. To further investigate the role of the pump, we have identified and characterized a novel ENU-induced mouse mutation, Tommy, in the PMCA2 gene.

Deletions and mutations in the acidic lipid-binding region of the plasma membrane Ca2+ pump: a study on different splicing variants of isoform 2.

Acidic phospholipids increase the affinity of the plasma membrane Ca(2+)-ATPase pump for Ca(2+). They interact with the C-terminal region of the pump and with a domain in the loop connecting transmembrane domains 2 and 3 (A(L) region) next to site A of alternative splicing. The contribution of the two phospholipid-binding sites and the possible interference of splicing inserts at site A with the regulation of the ATPase activity of isoform 2 of the pump by phospholipids have been analyzed.

Screening for GJB2 and GJB6 gene mutations in patients from Campania region with sensorineural hearing loss.

The aim of this study was to screen 349 patients affected by sensorineural hearing loss (SNHL), mostly from the Campania region (southern Italy), for GJB2 gene mutations and for two deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854). We identified pathogenetic GJB2 mutations in 51 cases (15% of patients). No GJB6 mutation was found.

Mammalian Pumilio 2 regulates dendrite morphogenesis and synaptic function.

In Drosophila, Pumilio (Pum) is important for neuronal homeostasis as well as learning and memory. We have recently characterized a mammalian homolog of Pum, Pum2, which is found in discrete RNA-containing particles in the somatodendritic compartment of polarized neurons. In this study, we investigated the role of Pum2 in developing and mature neurons by RNA interference.

The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss.

Progressive hearing loss is common in the human population, but we have few clues to the molecular basis. Mouse mutants with progressive hearing loss offer valuable insights, and ENU (N-ethyl-N-nitrosourea) mutagenesis is a useful way of generating models. We have characterised a new ENU-induced mouse mutant, Oblivion (allele symbol Obl), showing semi-dominant inheritance of hearing impairment.

The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation.

Most important processes in cell life are regulated by calcium (Ca2+). A number of mechanisms have thus been developed to maintain the concentration of free Ca2+ inside cells at the level (100-200nM) necessary for the optimal operation of the targets of its regulatory function. The systems that move Ca2+ back and forth across membranes are important actors in its control.

Inhibitory interaction of the 14-3-3 proteins with ubiquitous (PMCA1) and tissue-specific (PMCA3) isoforms of the plasma membrane Ca2+ pump.

A previous study has demonstrated that the ubiquitous plasma membrane Ca(2+) pump PMCA4 interacted with isoform epsilon of the 14-3-3 protein, whereas the nervous tissue-specific PMCA2 did not. The 14-3-3 proteins are widely expressed small acidic proteins, which modulate cell signaling, intracellular trafficking, transcription and apoptosis. The investigation has been extended to the other tissue-restricted pump (PMCA3) and to the other ubiquitous pump (PMCA1).

Functional specificity of PMCA isoforms?

In mammals, four different genes encode four PMCA isoforms. PMCA1 and PMCA4 are expressed ubiquitously. PMCA2 and PMCA3 are expressed prevalently in the central nervous systems.

Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11).

We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA.

Audiometric evaluation of carriers of the connexin 26 mutation 35delG.

Mutation in a gap junction protein gene (GJB2 also named connexin 26) is a major cause of autosomal recessive congenital deafness, which is responsible for about 80% of the cases in Mediterranean families, but actually little is known about the influence of GJB2 mutations on the hearing of obligate carriers. We examined GJB2 35delG mutation carrier individuals to test the possible presence and incidence of audiometric abnormalities among carriers of 35delG mutations. Tonal audiometric analysis was performed on a 35delG mutation carrier group (H) and on a non-carrier control group (N).

Down-regulation of otospiralin mRNA in response to acoustic stress in guinea pig.

Noise over-stimulation will induce or influence molecular pathways in the cochlea; one approach to the identification of the components of these pathways in the cochlea is to examine genes and proteins that change following different types and levels of stress. Quantitative reverse transcription polymerase chain reaction provides a method to look at differential expression of genes in the acoustic stress response. By using this technique we have revealed a down-regulation of the level of otospiralin mRNA in the cochlea of guinea pigs after white noise over-stimulation for 2 h at 108 dB SPL.

Human synaptobrevin-like 1 gene basal transcription is regulated through the interaction of selenocysteine tRNA gene transcription activating factor-zinc finger 143 factors with evolutionary conserved cis-elements.

The synaptobrevin-like 1 (SYBL1) gene is ubiquitously expressed and codes for an unusual member of the v-SNAREs molecules implicated in cellular exocytosis. This X-linked gene has the peculiarity of also being present on the Y chromosome in a transcriptional inactive status. Moreover, although ubiquitous, the function of SYBL1 is prominent in specific tissues, such as brain.

Otosclerosis: exclusion of linkage to the OTSC1 and OTSC2 loci in four Italian families.

Otosclerosis is the single most common cause of hearing impairment among adult caucasians. Little is known about its aetiology and its molecular aspects. Until now, genetic linkage in otosclerosis has been demonstrated in an Indian family and a Belgian family, showing the presence of two otosclerosis loci, OTSC1 and OTSC2, respectively.