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https://www.readbyqxmd.com/read/28648462/cyclic-tetrapeptide-hdac-inhibitors-as-potential-therapeutics-for-spinal-muscular-atrophy-screening-with-ipsc-derived-neuronal-cells
#1
Jiun-I Lai, Luke J Leman, Sherman Ku, Chris J Vickers, Christian A Olsen, Ana Montero, M Reza Ghadiri, Joel M Gottesfeld
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard...
June 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#2
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28642865/spinal-muscular-atrophy-from-defective-chaperoning-of-snrnp-assembly-to-neuromuscular-dysfunction
#3
REVIEW
Maia Lanfranco, Neville Vassallo, Ruben J Cauchi
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28639617/gene-therapy-for-spinomuscular-atrophy-a-biomedical-advance-a-missed-opportunity-for-more-equitable-drug-pricing
#4
T Friedmann
An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease...
June 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28637748/impaired-spliceosomal-usnrnp-assembly-leads-to-sm-mrna-down-regulation-and-sm-protein-degradation
#5
Archana Bairavasundaram Prusty, Rajyalakshmi Meduri, Bhupesh Kumar Prusty, Jens Vanselow, Andreas Schlosser, Utz Fischer
Specialized assembly factors facilitate the formation of many macromolecular complexes in vivo. The formation of Sm core structures of spliceosomal U-rich small nuclear ribonucleoprotein particles (UsnRNPs) requires assembly factors united in protein arginine methyltransferase 5 (PRMT5) and survival motor neuron (SMN) complexes. We demonstrate that perturbations of this assembly machinery trigger complex cellular responses that prevent aggregation of unassembled Sm proteins. Inactivation of the SMN complex results in the initial tailback of Sm proteins on the PRMT5 complex, followed by down-regulation of their encoding mRNAs...
June 21, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28637335/astrocyte-produced-mir-146a-as-a-mediator-of-motor-neuron-loss-in-spinal-muscular-atrophy
#6
Samantha L Sison, Teresa N Patitucci, Emily R Seminary, Eric Villalon, Christian L Lorson, Allison D Ebert
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28635376/advances-in-understanding-the-role-of-disease-associated-proteins-in-spinal-muscular-atrophy
#7
Seyyedmohsen Hosseinibarkooie, Svenja Schneider, Brunhilde Wirth
Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by alpha motor neuron loss in the spinal cord due to reduced survival of motor neuron (SMN) protein level. While the genetic basis of SMA is well described, the specific molecular pathway underlying SMA is still not fully understood. Areas covered: This review discusses the recent advancements in understanding the molecular pathways in SMA using different omics approaches and genetic modifiers identified in both vertebrate and invertebrate systems...
June 21, 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28634272/the-secreted-msp-domain-of-c-elegans-vapb-homolog-vpr-1-patterns-the-adult-striated-muscle-mitochondrial-reticulum-via-smn-1
#8
Jessica Schultz, Se-Jin Lee, Tim Cole, Hieu D Hoang, Jack Vibbert, Pauline A Cottee, Michael A Miller, Sung Min Han
The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid...
June 15, 2017: Development
https://www.readbyqxmd.com/read/28624227/efficient-smn-rescue-following-subcutaneous-tricyclo-dna-antisense-oligonucleotide-treatment
#9
Valérie Robin, Graziella Griffith, John-Paul L Carter, Christian J Leumann, Luis Garcia, Aurélie Goyenvalle
Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623256/lna-dna-mixmer-based-antisense-oligonucleotides-correct-alternative-splicing-of-the%C3%A2-smn2-gene-and-restore-smn-protein-expression-in-type-1-sma-fibroblasts
#10
Aleksander Touznik, Rika Maruyama, Kana Hosoki, Yusuke Echigoya, Toshifumi Yokota
Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28604635/splice-switching-therapy-for-spinal-muscular-atrophy
#11
REVIEW
Katharina E Meijboom, Matthew J A Wood, Graham McClorey
Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA...
June 12, 2017: Genes
https://www.readbyqxmd.com/read/28600679/resting-state-bold-oscillation-frequency-predicts-vigilance-task-performance-at-both-normal-and-high-environmental-temperatures
#12
Xiaopeng Song, Shaowen Qian, Kai Liu, Shuqin Zhou, Huaiqiu Zhu, Qihong Zou, Yijun Liu, Gang Sun, Jia-Hong Gao
Hyperthermia may impair vigilance functions and lead to slower reaction times (RTs) in the psychomotor vigilance task (PVT) and possibly disturbing cerebral hemodynamic rhythms. To test these hypotheses, we acquired the resting-state BOLD and cerebral blood flow (CBF) data, as well as PVTRTs from 15 participants in two simulated environmental thermal conditions (50 °C/25 °C). We adopted a data-driven method, frequency component analysis, to quantify the mean frequency of the BOLD series of each voxel. Across-subject correlation analysis was employed to detect the brain areas whose BOLD oscillation frequency was correlated with the RTs...
June 9, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28598854/analysis-of-azithromycin-monohydrate-as-a-single-or-a-combinatorial-therapy-in-a-mouse-model-of-severe-spinal-muscular-atrophy
#13
Erkan Y Osman, Charles W Washington, Madeline E Simon, Dalia Megiddo, Dalia Hagar Greif, Christian L Lorson
BACKGROUND: Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides...
June 9, 2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28598128/-molecular-features-of-sma-related-genes-in-spinal-muscular-atrophy-patients-of-han-nationality-in-southwest-china
#14
Min-Jin Wang, Jun Wang, Meng-Ge Bai, Wen-Jing Zhou, Li-Juan Wu, Si-Shi Tang, Xiao-Jun Lu, Bin-Wu Ying
OBJECTIVES: To investigate the molecular features of spinal muscular atrophy (SMA) related genes in SMA patients of Han nationality of southwest of China. METHODS: We collected 62 unrelated patients of SMA and 50 unrelated healthy individuals in this study.The copy numbers of survival motor neuron gene (SMN) and uronal-apoptosis inhibitory protein gene (NAIP) were measured by using multiplex ligation-dependent probe amplification (MLPA). RESULTS: Of 62 patients,the copy number of SMA1-4 were 30...
November 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28582530/an-in-vivo-genetic-screen-for-genes-involved-in-spliced-leader-trans-splicing-indicates-a-crucial-role-for-continuous-de-novo-spliced-leader-rnp-assembly
#15
Lucas Philippe, George C Pandarakalam, Rotimi Fasimoye, Neale Harrison, Bernadette Connolly, Jonathan Pettitt, Berndt Müller
Spliced leader (SL) trans-splicing is a critical element of gene expression in a number of eukaryotic groups. This process is arguably best understood in nematodes, where biochemical and molecular studies in Caenorhabditis elegans and Ascaris suum have identified key steps and factors involved. Despite this, the precise details of SL trans-splicing have yet to be elucidated. In part, this is because the systematic identification of the molecules involved has not previously been possible due to the lack of a specific phenotype associated with defects in this process...
June 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28570645/how-do-sma-linked-mutations-of-smn1-lead-to-structural-functional-deficiency-of-the-sma-protein
#16
Wei Li
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (∼95% of SMA cases) or mutation (∼5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are described in this article...
2017: PloS One
https://www.readbyqxmd.com/read/28561813/therapeutic-approaches-for-spinal-muscular-atrophy-sma
#17
REVIEW
M Scoto, R S Finkel, E Mercuri, F Muntoni
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1...
May 31, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28559843/altered-functional-connectivity-of-cognitive-related-cerebellar-subregions-in-alzheimer-s-disease
#18
Weimin Zheng, Xingyun Liu, Haiqing Song, Kuncheng Li, Zhiqun Wang
Alzheimer's disease (AD) is the most common cause of dementia. Previous studies have found disrupted resting state functional connectivities (rsFCs) in various brain networks in the AD patients. However, few studies have focused on the rsFCs of the cerebellum and its sub-regions in the AD patients. In this study, we collected resting-state functional magnetic resonance imaging (rs-fMRI) data including 32 AD patients and 38 healthy controls (HCs). We selected two cognitive-related subregions of the cerebellum as seed region and mapped the whole-brain rsFCs for each subregion...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28556834/developmental-regulation-of-smn-expression-pathophysiological-implications-and-perspectives-for-therapy-development-in-spinal-muscular-atrophy
#19
REVIEW
S Jablonka, M Sendtner
Spinal muscular atrophy (SMA), the predominant form of motoneuron diease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction...
May 30, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28542928/crosstalk-between-e2f1-and-p53-transcription-factors-in-doxorubicin-induced-dna-damage-evidence-for-preventive-protective-effects-of-silymarin
#20
Seyedeh-Khadijeh Shafiei-Roudbari, Hassan Malekinejad, Hamed Janbaz-Aciabar, Mazdak Razi
OBJECTIVES: To study the effects of silymarin in various forms of applications on the molecular mechanism(s) of doxorubicin-induced testicular toxicity in male rats. METHODS: Following DOX administration with or without SMN in male rats, sperm quality assays were conducted. Moreover, total antioxidant capacity and nitric oxide content of testis were determined. Expression profile of p53 and E2F1 was analysed by PCR technique. Ultimately, the rate of DNA fragmentation in the testes was quantitatively measured...
May 23, 2017: Journal of Pharmacy and Pharmacology
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