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.

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 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

scholarly journals In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 712
Author(s):  
Ji-Hea Yu ◽  
Bae-Geun Nam ◽  
Min-Gi Kim ◽  
Soonil Pyo ◽  
Jung-Hwa Seo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Fate ◽  
Gabaergic Neurons ◽  
Oligodendrocyte Progenitor Cells ◽  
Adeno Associated Virus ◽  
In Vivo Expression ◽  
Transcription Factor 4 ◽  
Phosphate Buffered Saline

White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4.

scholarly journals Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum

2003 ◽  
Vol 85 (4) ◽  
pp. 1054-1063 ◽  
Author(s):  
J. M. Vetter ◽  
T. Jehle ◽  
J. Heinemeyer ◽  
P. Franz ◽  
P. F. Behrens ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Synaptic Function ◽  
Exon 1

scholarly journals Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

2021 ◽  
Vol 14 (10) ◽  
pp. 1044
Author(s):  
Letizia Pruccoli ◽  
Carlo Breda ◽  
Gabriella Teti ◽  
Mirella Falconi ◽  
Flaviano Giorgini ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Positive Impact ◽  
Neuroprotective Effects ◽  
Drosophila Model ◽  
Exon 1 ◽  
Transgenic Drosophila

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD.

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 The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Annika Heinz ◽  
Judith Schilling ◽  
Willeke van Roon-Mom ◽  
Sybille Krauß
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein A ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Progressive Movement ◽  
Promising Therapeutic Target ◽  
Promising Therapeutic Approach ◽  
Exon 1 ◽  
Polyglutamine Protein

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

scholarly journals The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

2019 ◽  
Vol 151 (4) ◽  
pp. 507-519 ◽  
Author(s):  
Erich E. Wanker ◽  
Anne Ast ◽  
Franziska Schindler ◽  
Philipp Trepte ◽  
Sigrid Schnoegl
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Mutant Huntingtin ◽  
Protein Protein Interactions ◽  
Huntingtin Protein ◽  
Mutant Huntingtin Protein
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