scholarly journals Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1418
Author(s):  
Ana F. Castro ◽  
Joana R. Loureiro ◽  
José Bessa ◽  
Isabel Silveira
Keyword(s):  
Gene Expression ◽  
Neuromuscular Diseases ◽  
Antisense Transcription ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7 ◽  
Repeat Expansions ◽  
Cellular Pathways ◽  
The Impact ◽  
Lateral Sclerosis

Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington’s disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies.

scholarly journals How Loan Bank of Assistive Technology Impacts on Life of Persons with Amyotrophic Lateral Sclerosis and Neuromuscular Diseases: A Collaborative Initiative

2021 ◽  
Vol 18 (2) ◽  
pp. 763
Author(s):  
Thais Pousada ◽  
Jessica Garabal-Barbeira ◽  
Cristina Martínez ◽  
Betania Groba ◽  
Laura Nieto-Riveiro ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Assistive Technology ◽  
Positive Impact ◽  
Outcome Measurement ◽  
Neuromuscular Diseases ◽  
Three Dimensions ◽  
Assistive Device ◽  
Cross Sectional ◽  
The Impact ◽  
Lateral Sclerosis

(1) Background: The study is focused on the implementation of outcome measurement tools to assess the impact of an assistive device from a loan bank in the lives of people with Amyotrophic Lateral Sclerosis and Neuromuscular Diseases. The secondary purpose is to analyse the correct matching between the person and technology, derived from the counselling of an occupational therapist. (2) Methods: Cross-sectional study. The sample was formed by 28 people with rare neurodegenerative disorders. A specific questionnaire, the Psychosocial Impact of Assistive Device Scale (PIADS), and the Matching Person and Technology (MPT) tool were applied to collect the data. (3) Results: The dimension of the PIADS with the best score was competence, and the variations according to gender were not remarkable. The three dimensions of the PIADS (competence, adaptability, and self-esteem) were correlated positively between them and with the mean score of the MPT tool (p < 0.01). The type of assistive technology (AT), diagnosis, and correct match between person–technology are the main factors that condition a positive impact. (4) Conclusions: The results noted the importance of assessing the needs, demands, and contexts of people with rare neurodegenerative diseases to prescribe the best AT. Loan banks of AT have to be considered a valid service that complements their lack in public health services.

scholarly journals Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

2020 ◽  
Vol 10 (4) ◽  
pp. 262
Author(s):  
Giovanna Morello ◽  
Giulia Gentile ◽  
Rossella Spataro ◽  
Antonio Gianmaria Spampinato ◽  
Maria Guarnaccia ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Spinocerebellar Ataxia ◽  
Complex Disease ◽  
Spinocerebellar Ataxia Type ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinocerebellar Ataxia Type 1 ◽  
Pathogenic Variants ◽  
Lateral Sclerosis

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

scholarly journals Psychosocial Stress and Cannabinoid Drugs Affect Acetylation of α-tubulin (K40) and Gene Expression in the Prefrontal Cortex of Adult Mice

2021 ◽  
Author(s):  
Jordi Tomas-Roig ◽  
Shyam Sundar Ramasamy ◽  
Diana Zbarsky ◽  
Ursula Havemann-Reinecke ◽  
Sigrid Hoyer-Fender
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Psychosocial Stress ◽  
Cannabinoid Receptor ◽  
Brain Plasticity ◽  
Receptor Type ◽  
Tubulin Acetylation ◽  
Cannabinoid Receptor Type 1 ◽  
The Impact

Abstract The dynamics of neuronal microtubules are essential for brain plasticity. Vesicular transport and synaptic transmission, additionally, requires acetylation of α-tubulin, and aberrant tubulin acetylation and neurobiological deficits are associated. Prolonged exposure to a stressor or consumption of drugs of abuse, like marihuana, lead to neurological changes and psychotic disorders. Here, we studied the effect of psychosocial stress and the administration of cannabinoid receptor type 1 drugs on α-tubulin acetylation in different brain regions of mice. We found significantly decreased tubulin acetylation in the prefrontal cortex and the dorsal striatum in stressed mice. The impact of cannabinoid drugs on stress-induced microtubule disturbance was investigated by administration of the cannabinoid receptor agonist WIN55,212-2 and/or antagonist rimonabant. In both, control and stressed mice, the administration of WIN55,212-2 significantly increased the tubulin acetylation in the prefrontal cortex whereas administration of both cannabinoid drugs acted antagonistically indicating a cannabinoid receptor type 1 mediated effect. The analysis of gene expression in the prefrontal cortex showed a consistent expression of ApoE attributable to either psychosocial stress or administration of the cannabinoid agonist. Additionally, ApoE expression inversely correlated with acetylated tubulin levels when comparing controls and stressed mice treated with WIN55,212-2 whereas rimonabant treatment showed the opposite.

scholarly journals The RNA helicase DHX36/G4R1 modulates C9orf72 GGGGCC repeat-associated translation

2021 ◽  
Author(s):  
Yi-Ju Tseng ◽  
Siara N. Sandwith ◽  
Katelyn M. Green ◽  
Antonio E. Chambers ◽  
Amy Krans ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Hexanucleotide Repeat ◽  
G Quadruplex ◽  
Therapeutic Development ◽  
Repeat Expansions ◽  
Nucleotide Repeats ◽  
The Impact ◽  
Lateral Sclerosis ◽  
Ran Translation

ABSTRACTGGGGCC (G4C2) hexanucleotide repeat expansions (HRE) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of this expansion generates toxic proteins that accumulate in patient brains and contribute to disease pathogenesis. The DEAH-Box Helicase 36 (DHX36/G4R1) plays active roles in RNA and DNA G-quadruplex (G4) resolution in cells. As G4C2 repeats form G4 structures in vitro, we sought to determine the impact of manipulating DHX36 expression on repeat transcription and RAN translation. We found that DHX36 depletion suppresses RAN translation from reporter constructs in a repeat length dependent manner while overexpression of DHX36 enhances RAN translation from G4C2 reporter RNAs. Taken together, these results suggest that DHX36 is active in regulating G4C2 repeat translation, providing potential implications for therapeutic development in nucleotide repeats expansion disorders.

scholarly journals Intrinsic Type 1 Interferon (IFN1) Profile of Uncultured Human Bone Marrow CD45lowCD271+ Multipotential Stromal Cells (BM-MSCs): The Impact of Donor Age, Culture Expansion and IFNα and IFNβ Stimulation

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 214
Author(s):  
Payal Ganguly ◽  
Agata Burska ◽  
Charlotte Davis ◽  
Jehan J. El-Jawhari ◽  
Peter V. Giannoudis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Gene Expression Signature ◽  
Proliferative Potential ◽  
Donor Age ◽  
Hematopoietic Stem ◽  
Type 1 Interferon ◽  
The Impact

Skeletal aging is associated with reduced proliferative potential of bone marrow (BM) multipotential stromal cells (MSCs). Recent data suggest the involvement of type 1 interferon (IFN1) signalling in hematopoietic stem cell (HSC) senescence. Considering that BM-HSCs and BM-MSCs share the same BM niche, we investigated IFN1 expression profile in human BM-MSCs in relation to donor age, culture-expansion and IFN1 (α and β) stimulation. Fluorescence-activated cell sorting was used to purify uncultured BM-MSCs from younger (19–41, n = 6) and older (59–89, n = 6) donors based on the CD45lowCD271+ phenotype, and hematopoietic-lineage cells (BM-HLCs, CD45+CD271−) were used as controls. Gene expression was analysed using integrated circuits arrays in sorted fractions as well as cultured/stimulated BM-MSCs and Y201/Y202 immortalised cell lines. IFN1 stimulation led to BM-MSC growth arrest and upregulation of many IFN1-stimulated genes (ISGs), with IFNβ demonstrating stronger effects. Uncultured MSCs were characterised by a moderate-level ISG expression similar to Y201 cells. Age-related changes in ISG expression were negligible in BM-MSCs compared to BM-HLCs, and intracellular reactive oxygen species (ROS) levels in BM-MSCs did not significantly correlate with donor age. Antiaging genes Klotho and SIRT6 correlated with more ISGs in BM-MSCs than in BM-HLCs. In patients with osteoarthritis (OA), BM-MSCs expressed considerably lower levels of several ISGs, indicating that their IFN1 signature is affected in a pathological condition. In summary, BM-MSCs possess homeostatic IFN1 gene expression signature in health, which is sensitive to in vitro culture and external IFN1 stimulation. IFN signalling may facilitate in vivo BM-MSC responses to DNA damage and combating senescence and aberrant immune activation.

scholarly journals Impact of SARS-CoV-2 Infection Among Non-Invasive Ventilated ALS Patients

2021 ◽  
pp. 1-3
Author(s):  
Miguel Oliveira Santos ◽  
Sara Domingues ◽  
Marta Gromicho ◽  
Susana Pinto ◽  
Mamede de Carvalho
Keyword(s):  
Age Of Onset ◽  
Severe Disease ◽  
Neuromuscular Diseases ◽  
Supplemental Oxygen ◽  
Total Recovery ◽  
Non Invasive ◽  
Respiratory Involvement ◽  
Als Patients ◽  
The Impact ◽  
Lateral Sclerosis

Background: The impact of SARS-CoV-2 infection among neuromuscular diseases with respiratory involvement, including amyotrophic lateral sclerosis (ALS), is still to be elucidated. Objectives: We aim to characterize the clinical outcome of ALS patients non-invasive ventilated (NIV), following SARS-CoV-2 infection. Methods: We analyzed retrospectively our patients followed regularly at our ALS clinic, from the beginning of the COVID-19 pandemic (middle March 2020) to March 2021. We included patients on NIV with a documented SARS-CoV-2 infection. We recorded demographic and clinical data, including from the acute infectious illness. Results: Three men with spinal-onset ALS are described, mean age of onset was 55±9.1 years (45–61), and mean disease duration was 17.5±15.9 months (6.1–41). All of them were wheelchair-bounded, with a mean ALSFRS-R of 15.3±0.6 (15–16). One patient used NIV 15 hours/day, 2 between 4 to 7 hours/day, and all used assisted coughing twice daily. None had coexistent comorbidities. They were managed for SARS-CoV-2 infection as outpatients with fluticasone, bronchodilators, azithromycin and increasing frequency of assisted coughing. Supplemental oxygen (mean of 2 liters per minute) was needed in two patients, and one required NIV also during the daytime. Total recovery from SARS-CoV-2 infection was observed in all, despite being in an advanced stage of their disease, with severe respiratory involvement. Conclusions: Prompt medical treatment is recommended for ALS patients with severe disease infected by SARS-CoV-2.

scholarly journals Non-ATG–initiated translation directed by microsatellite expansions

2010 ◽  
Vol 108 (1) ◽  
pp. 260-265 ◽  
Author(s):  
Tao Zu ◽  
Brian Gibbens ◽  
Noelle S. Doty ◽  
Mário Gomes-Pereira ◽  
Aline Huguet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Start Codon ◽  
Spinocerebellar Ataxia Type ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Polyglutamine Expansion ◽  
Transfected Cells ◽  
Cag Expansion ◽  
Ran Translation

Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.

scholarly journals ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Gijs H P Tazelaar ◽  
Steven Boeynaems ◽  
Mathias De Decker ◽  
Joke J F A van Vugt ◽  
Lindy Kool ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
International Study ◽  
Spinocerebellar Ataxia Type ◽  
Published Data ◽  
Polyglutamine Expansions ◽  
Similar Disease ◽  
Repeat Expansions ◽  
Lateral Sclerosis

Abstract Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

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