scholarly journals Berichtigung: One-Pot Semisynthesis of Exon 1 of the Huntingtin Protein: New Tools for Elucidating the Role of Posttranslational Modifications in the Pathogenesis of Huntington’s Disease

2014 ◽  
Vol 126 (29) ◽  
pp. 7517-7517
Author(s):  
Annalisa Ansaloni ◽  
Zhe-Ming Wang ◽  
Jae Sun Jeong ◽  
Francesco Simone Ruggeri ◽  
Giovanni Dietler ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Posttranslational Modifications ◽  
One Pot ◽  
Huntingtin Protein ◽  
Exon 1

One-Pot Semisynthesis of Exon 1 of the Huntingtin Protein: New Tools for Elucidating the Role of Posttranslational Modifications in the Pathogenesis of Huntington’s Disease

2014 ◽  
Vol 126 (7) ◽  
pp. 1959-1964 ◽  
Author(s):  
Annalisa Ansaloni ◽  
Zhe-Ming Wang ◽  
Jae Sun Jeong ◽  
Francesco Simone Ruggeri ◽  
Giovanni Dietler ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Posttranslational Modifications ◽  
One Pot ◽  
Huntingtin Protein ◽  
Exon 1

scholarly journals Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12499
Author(s):  
Chaebin Kim ◽  
Ali Yousefian-Jazi ◽  
Seung-Hye Choi ◽  
Inyoung Chang ◽  
Junghee Lee ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Involuntary Movement ◽  
Therapeutic Approaches ◽  
Exon 1 ◽  
Human Chromosome 4 ◽  
The Brain

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

scholarly journals Phosphorylation of huntingtin at residue T3 is decreased in Huntington’s disease and modulates mutant huntingtin protein conformation

2017 ◽  
Vol 114 (50) ◽  
pp. E10809-E10818 ◽  
Author(s):  
Cristina Cariulo ◽  
Lucia Azzollini ◽  
Margherita Verani ◽  
Paola Martufi ◽  
Roberto Boggio ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Protein Conformation ◽  
Clinical Samples ◽  
Biophysical Properties ◽  
Mutant Huntingtin Protein ◽  
Exon 1 ◽  
Bona Fide

Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington’s disease models and in Huntington’s disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington’s disease.

scholarly journals An Intrabody Drug (rAAV6-INT41) Reduces the Binding of N-Terminal Huntingtin Fragment(s) to DNA to Basal Levels in PC12 Cells and Delays Cognitive Loss in the R6/2 Animal Model

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
I. Alexandra Amaro ◽  
Lee A. Henderson
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Progressive Disease ◽  
Nuclear Translocation ◽  
Adeno Associated Virus ◽  
Huntingtin Protein ◽  
Fusion Construct ◽  
Gene Dysregulation ◽  
Exon 1 ◽  
Proline Rich Region

Huntington’s disease (HD) is a fatal progressive disease linked to expansion of glutamine repeats in the huntingtin protein and characterized by the progressive loss of cognitive and motor function. We show that expression of a mutant human huntingtin exon-1-GFP fusion construct results in nonspecific gene dysregulation that is significantly reduced by 50% due to coexpression of INT41, an intrabody specific for the proline-rich region of the huntingtin protein. Using stable PC12 cell lines expressing either inducible human mutant huntingtin (mHtt, Q73) or normal huntingtin (nHtt, Q23), we investigated the effect of rAAV6-INT41, an adeno-associated virus vector with the INT41 coding sequence, on the subcellular distribution of Htt. Compartmental fractionation 8 days after induction of Htt showed a 6-fold increased association of a dominate N-terminal mHtt fragment with DNA compared to N-terminal nHtt. Transduction with rAAV6-INT41 reduced DNA binding of N-terminal mHtt 6.5-fold in the nucleus and reduced nuclear translocation of the detected fragments. Subsequently, when rAAV6-INT41 is delivered to the striatum in the R6/2 mouse model, treated female mice exhibited executive function statistically indistinguishable from wild type, accompanied by reductions in Htt aggregates in the striatum, suggesting that rAAV6-INT41 is promising as a gene therapy for Huntington’s disease.

scholarly journals Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

2016 ◽  
Vol 113 (20) ◽  
pp. 5736-5741 ◽  
Author(s):  
Aldrin E. Molero ◽  
Eduardo E. Arteaga-Bracho ◽  
Christopher H. Chen ◽  
Maria Gulinello ◽  
Michael L. Winchester ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Coordination ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Polyglutamine Expansion ◽  
Exon 1 ◽  
Stem Cell Lines ◽  
Characteristic Features

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington’s disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.

The Role of Melatonin in Multiple Sclerosis, Huntington's Disease and Cerebral Ischemia

2014 ◽  
Vol 13 (6) ◽  
pp. 1096-1119 ◽  
Author(s):  
Begona Escribano ◽  
Ana Colin-Gonzalez ◽  
Abel Santamaria ◽  
Isaac Tunez
Keyword(s):  
Multiple Sclerosis ◽  
Cerebral Ischemia ◽  
Huntington's Disease ◽  
Huntington’S Disease

scholarly journals The Role of Pretraining on Skilled Forelimb Use in an Animal Model of Huntington's Disease

2003 ◽  
Vol 12 (3) ◽  
pp. 257-264 ◽  
Author(s):  
R. A. Fricker-Gates ◽  
R. Smith ◽  
J. Muhith ◽  
S. B. Dunnett
Keyword(s):  
Animal Model ◽  
Huntington's Disease ◽  
Huntington’S Disease
Sign in / Sign up

Export Citation Format

Share Document