scholarly journals The Role of the Immune System in Triplet Repeat Expansion Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Marta Olejniczak ◽  
Martyna O. Urbanek ◽  
Wlodzimierz J. Krzyzosiak
Keyword(s):  
Immune System ◽  
Trinucleotide Repeat ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Triplet Repeat ◽  
Triplet Repeat Expansion ◽  
Polyglutamine Disorders ◽  
Intracellular Aggregates

Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

scholarly journals HDAC3 deacetylates the DNA mismatch repair factor MutSβ to stimulate triplet repeat expansions

2020 ◽  
Vol 117 (38) ◽  
pp. 23597-23605 ◽  
Author(s):  
Gregory M. Williams ◽  
Vasileios Paschalis ◽  
Janice Ortega ◽  
Frederick W. Muskett ◽  
James T. Hodgkinson ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Trinucleotide Repeat ◽  
Age Of Onset ◽  
Neurological Diseases ◽  
Inhibitory Effect ◽  
Repeat Expansion ◽  
Triplet Repeat ◽  
Lysine Residues ◽  
Repeat Expansions ◽  
Repair Factor

Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.

Myotonic dystrophy type 1 (DM1): A triplet repeat expansion disorder

Gene ◽  
2013 ◽  
Vol 522 (2) ◽  
pp. 226-230 ◽  
Author(s):  
Ashok Kumar ◽  
Sarita Agarwal ◽  
Divya Agarwal ◽  
Shubha R. Phadke
Keyword(s):  
Myotonic Dystrophy ◽  
Repeat Expansion ◽  
Triplet Repeat ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Triplet Repeat Expansion

204. Isolation of CAG repeat containing genes from human placenta and decidua

2005 ◽  
Vol 17 (9) ◽  
pp. 77
Author(s):  
K. A. Freed ◽  
S. P. Brennecke ◽  
E. K. Moses
Keyword(s):  
Mutation Rate ◽  
Dna Sequences ◽  
Human Placenta ◽  
Trinucleotide Repeat ◽  
Normal Population ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
High Mutation Rate ◽  
Strong Negative Selection ◽  
Expansion Mutation

Pre-eclampsia is a serious disorder of pregnancy that manifests clinically in the mother as new-onset hypertension and proteinuria. Although the precise cause remains unknown, the placenta and the decidua play a fundamental role. The worldwide incidence of pre-eclampsia is 2–5% and such a high incidence, in the face of strong negative selection, suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. In these diseases repeated trinucleotide DNA sequences within specific genes multiply or expand up to 1000-fold. The result of this gene expansion/mutation is altered gene function that confers genetic susceptibility. Thus, the overall objective of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-eclampsia. The specific aim of this study was to isolate CAG repeat containing genes from human placenta and decidua. An adaptation of the mRNA differential display technique and traditional cDNA library screening was used. In total, 72 placental and 51 decidual sequences were analyzed using the BLAST nucleotide comparison program. Five cDNAs were analyzed further. The unique sequences surrounding the CAG repeat regions of these five genes will be used to generate primers to ascertain if any of these repeat DNA sequences vary in number in the normal population. If polymorphic genes are identified, the primers will be used on pre-eclamptic pedigrees to determine if pre-eclampsia is associated with a repeat expansion mutation.

A Single-Surface Electrochemical Biosensor for the Detection of DNA Triplet Repeat Expansion

2006 ◽  
Vol 18 (2) ◽  
pp. 141-151 ◽  
Author(s):  
Miroslav Fojta ◽  
Petra Brázdilová ◽  
Kateřina Cahová ◽  
Petr Pečinka
Keyword(s):  
Electrochemical Biosensor ◽  
Repeat Expansion ◽  
Triplet Repeat ◽  
Triplet Repeat Expansion
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