scholarly journals Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

2021 ◽  
Author(s):  
Lydia M. Castelli ◽  
Wan-Ping Huang ◽  
Ya-Hui Lin ◽  
Kung-Yao Chang ◽  
Guillaume M. Hautbergue
Keyword(s):  
Molecular Mechanisms ◽  
Low Complexity ◽  
Spinocerebellar Ataxia Type ◽  
Rna Structures ◽  
Therapeutic Approaches ◽  
Future Directions ◽  
Coding Regions ◽  
Hexanucleotide Repeat ◽  
Ran Translation

Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

scholarly journals Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

2014 ◽  
Author(s):  
Rajesh Menon ◽  
Daniel Soong ◽  
Cesira de Chiara ◽  
Mark Holt ◽  
John McCormick ◽  
...  
Keyword(s):  
Low Complexity ◽  
The Self ◽  
Spinocerebellar Ataxia Type ◽  
Aggregation Process ◽  
Combined Approach ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Tract ◽  
Self Association

The neurodegenerative spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.

scholarly journals Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

2014 ◽  
Author(s):  
Rajesh Menon ◽  
Daniel Soong ◽  
Cesira de Chiara ◽  
Mark Holt ◽  
John McCormick ◽  
...  
Keyword(s):  
Low Complexity ◽  
The Self ◽  
Spinocerebellar Ataxia Type ◽  
Aggregation Process ◽  
Combined Approach ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Tract ◽  
Self Association

The neurodegenerative spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.

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.

Molecular Mechanisms of Spinocerebellar Ataxia Type 1

2020 ◽  
Vol 56 (2) ◽  
pp. 129-141
Author(s):  
E. A. Volovikov ◽  
A. V. Davidenko ◽  
M. A. Lagarkova
Keyword(s):  
Spinocerebellar Ataxia ◽  
Molecular Mechanisms ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1

scholarly journals Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

2014 ◽  
Author(s):  
Rajesh Menon ◽  
Daniel Soong ◽  
Cesira de Chiara ◽  
Mark Holt ◽  
John McCormick ◽  
...  
Keyword(s):  
Low Complexity ◽  
The Self ◽  
Spinocerebellar Ataxia Type ◽  
Aggregation Process ◽  
Combined Approach ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Tract ◽  
Self Association

The neurodegenerative spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.

scholarly journals Gene Therapy for Heart Disease: Modified mRNA Perspectives

2021 ◽  
Author(s):  
Lior Zangi ◽  
Ravinder K. Kaundal ◽  
Keerat Kaur
Keyword(s):  
Gene Therapy ◽  
Heart Disease ◽  
Molecular Mechanisms ◽  
Cardiac Repair ◽  
The Body ◽  
Therapeutic Approaches ◽  
Delivery Methods ◽  
Future Directions ◽  
Promising Alternative ◽  
Compositional Changes

Ischemic heart disease (IHD) presents a gigantic clinical challenge that demands effective therapeutic approaches. With increasing knowledge of the basic molecular mechanisms guiding the progress of this disease, it is now possible to target the key pathological players through gene therapy. Modified mRNA-based gene delivery presents a promising alternative to traditional gene therapy, because modRNA approaches have high potency, non-immunogenicity, greater efficiency and controlled nucleic acid transfer to the body. However, until recently the therapeutic applications of mRNA have been limited, as naturally occurring mRNA is rapidly degraded and cleared from the circulation. In this chapter, we outline the compositional changes made to mRNA to enhance its translational capacity and discuss the available carrier molecules currently being employed to deliver modRNA to the heart. We provide a detailed overview of modRNA applicability for cardiac repair and regeneration and consider future directions for novel delivery methods that can facilitate its cardiac therapeutic use.

scholarly journals Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2944 ◽  
Author(s):  
Olga Tarasova ◽  
Sergey Ivanov ◽  
Dmitry A. Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Molecular Mechanisms ◽  
Antiretroviral Drugs ◽  
Molecular Pathways ◽  
Therapeutic Approaches ◽  
Immunodeficiency Virus ◽  
Cycle Regulation ◽  
Text And Data Mining ◽  
Hiv 1

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.

scholarly journals Regulation of Posttranscriptional Modification as a Possible Therapeutic Approach for Retinal Neuroprotection

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yoko Ozawa ◽  
Toshihide Kurihara ◽  
Kazuo Tsubota ◽  
Hideyuki Okano
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Synaptic Activity ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Ubiquitin Proteasome

Understanding pathogenesis at the molecular level is the first step toward developing new therapeutic approaches. Here, we review the molecular mechanisms of visual dysfunction in two common diseases, innate chorioretinal inflammation and diabetic retinopathy, and the role of the ubiquitin-proteasome system (UPS) in both processes. In innate chorioretinal inflammation, interleukin-6 family ligands induce STAT3 activation in photoreceptors, which causes UPS-mediated excessive degradation of the visual substance, rhodopsin. In diabetic retinopathy, angiotensin II type 1 receptor (AT1R) signaling activates ERK in the inner layers of the retina, causing UPS-mediated excessive degradation of the synaptic vesicle protein, synaptophysin. This latter effect may decrease synaptic activity, in turn adversely affecting neuronal survival. Both mechanisms involve increased UPS activity and the subsequent excessive degradation of a protein required for visual function. Finally, we review the therapeutic potential of regulating the UPS to protect tissue function, citing examples from clinical applications in other medical fields.

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