scholarly journals A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington's disease

2021 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jonathan Bard ◽  
Manuela Hessmann ◽  
Longbin Liu ◽  
Annette Gaertner ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Interventions ◽  
Non Invasive ◽  
Positron Emission ◽  
Trinucleotide Expansion ◽  
Imaging Markers ◽  
The Brain ◽  
Polyq Tract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

scholarly journals Huntington's Disease: An Immune Perspective

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Annapurna Nayak ◽  
Rafia Ansar ◽  
Sunil K. Verma ◽  
Domenico Marco Bonifati ◽  
Uday Kishore
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Typical Feature ◽  
Trinucleotide Repeats ◽  
Mutant Huntingtin Protein ◽  
Unexplored Area ◽  
Cag Trinucleotide Repeats ◽  
The Brain ◽  
Abnormal Expansion

Huntington's disease (HD) is a progressive neurodegenerative disorder that is caused by abnormal expansion of CAG trinucleotide repeats. Neuroinflammation is a typical feature of most neurodegenerative diseases that leads to an array of pathological changes within the affected areas in the brain. The neurodegeneration in HD is also caused by aberrant immune response in the presence of aggregated mutant huntingtin protein. The effects of immune activation in HD nervous system are a relatively unexplored area of research. This paper summarises immunological features associated with development and progression of HD.

scholarly journals Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Marta Valenza ◽  
Ilaria Ottonelli ◽  
Alice Passoni ◽  
Monica Favagrossa ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Polymeric Nanoparticles ◽  
Cholesterol Biosynthesis ◽  
Hybrid Nanoparticles ◽  
Neural Cells ◽  
Peripheral Tissues ◽  
Brain Cholesterol ◽  
The Brain

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

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 Implications of the Orb2 Amyloid Structure in Huntington’s Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6910
Author(s):  
Rubén Hervás ◽  
Alexey G. Murzin ◽  
Kausik Si
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Autosomal Dominant ◽  
Neurodegenerative Disorder ◽  
Structural Data ◽  
Cag Repeat ◽  
Functional Amyloid ◽  
Drosophila Brain ◽  
Structural Insight ◽  
The Brain

Huntington’s disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington’s disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain.

scholarly journals Regulation of P-glycoprotein expression in brain capillaries in Huntington’s disease and its impact on brain availability of antipsychotic agents risperidone and paliperidone

2015 ◽  
Vol 36 (8) ◽  
pp. 1412-1423 ◽  
Author(s):  
Yu-Han Kao ◽  
Yijuang Chern ◽  
Hui-Ting Yang ◽  
Hui-Mei Chen ◽  
Chun-Jung Lin
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mrna Level ◽  
Antipsychotic Agents ◽  
Brain Capillaries ◽  
P Glycoprotein ◽  
Exogenous Expression ◽  
And Function ◽  
The Brain ◽  
Polyq Tract

Huntington’s disease (HD) is a neurodegenerative disease marked by an expanded polyglutamine (polyQ) tract on the huntingtin (HTT) protein that may cause transcriptional dysfunction. This study aimed to investigate the regulation and function of P-glycoprotein, an important efflux transporter, in brain capillaries in HD. The results showed that, compared with the littermate controls, R6/2 HD transgenic mice with the human mutant HTT gene had higher levels of P-glycoprotein mRNA and protein and enhanced NF-κB activity in their brain capillaries. Higher P-glycoprotein expression was also observed in the brain capillaries of human HD patients. Consistent with this enhanced P-glycoprotein expression, brain extracellular levels and brain-to-plasma ratios of the antipsychotic agents risperidone and paliperidone were significantly lower in R6/2 mice than in their littermate controls. Exogenous expression of human mutant HTT protein with expanded polyQ (mHTT-109Q) in HEK293T cells enhanced the levels of P-glycoprotein transcripts and NF-κB activity compared with cells expressing normal HTT-25Q. Treatment with the IKK inhibitor, BMS-345541, decreased P-glycoprotein mRNA level in cells transfected with mHTT-109Q or normal HTT-25Q. In conclusion, mutant HTT altered the expression of P-glycoprotein through the NF-κB pathway in brain capillaries in HD and markedly affected the availability of P-glycoprotein substrates in the brain.

scholarly journals Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases

2005 ◽  
Vol 169 (4) ◽  
pp. 647-656 ◽  
Author(s):  
Shouqing Luo ◽  
Coralie Vacher ◽  
Janet E. Davies ◽  
David C. Rubinsztein
Keyword(s):  
Amino Acids ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Membrane ◽  
Aggregate Formation ◽  
Polyq Tract ◽  
Polyq Expansion ◽  
In Cells

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. Mutant htt toxicity is exposed after htt cleavage by caspases and other proteases release NH2-terminal fragments containing the polyQ expansion. Here, we show htt interacts and colocalizes with cdk5 in cellular membrane fractions. Cdk5 phosphorylates htt at Ser434, and this phosphorylation reduces caspase-mediated htt cleavage at residue 513. Reduced mutant htt cleavage resulting from cdk5 phosphorylation attenuated aggregate formation and toxicity in cells expressing the NH2-terminal 588 amino acids (htt588) of mutant htt. Cdk5 activity is reduced in the brains of HD transgenic mice compared with controls. This result can be accounted for by the polyQ-expanded htt fragments reducing the interaction between cdk5 and its activator p35. These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt.

scholarly journals Huntington’s Disease: A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 482 ◽  
Author(s):  
Klaudia Cybulska ◽  
Lars Perk ◽  
Jan Booij ◽  
Peter Laverman ◽  
Mark Rijpkema
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Imaging Biomarkers ◽  
Medium Spiny Neurons ◽  
Non Invasive ◽  
Positron Emission ◽  
Cag Expansion ◽  
Recent Developments ◽  
Mutant Huntingtin Protein ◽  
Expansion Mutation

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.

scholarly journals iNKT Cell Activation Exacerbates the Development of Huntington’s Disease in R6/2 Transgenic Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Hyun Jung Park ◽  
Sung Won Lee ◽  
Wooseok Im ◽  
Manho Kim ◽  
Luc Van Kaer ◽  
...  
Keyword(s):  
Immune System ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Inkt Cells ◽  
Regulatory T Lymphocytes ◽  
The Brain ◽  
Invariant Natural Killer

Huntington’s disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFNγ and IL4 upon stimulation with the glycolipid α-galactosylceramide (α-GalCer). By employing both R6/2 Tg mice (murine HD model) and Jα18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that Jα18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with α-GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated α-GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.

scholarly journals Distribution of Huntington’s disease Haplogroups in Indian population

2021 ◽  
Author(s):  
Sowmya Devatha Venkatesh ◽  
Nikhil Ratna ◽  
Swathi Lakshmi.P ◽  
Geetanjali Murari ◽  
Nitish Kamble ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Indian Population ◽  
Autosomal Dominant ◽  
Neurodegenerative Disorder ◽  
Informative Snps ◽  
Genotype Frequencies ◽  
Trinucleotide Expansion

AbstractHuntington’s disease (HD), a rare neurodegenerative disorder, is inherited in an autosomal dominant manner, and caused by a pathological trinucleotide expansion at exon1 of the HTT locus. Previous studies have described the haplogroups at the HTT locus that can explain the differences in prevalence of HD. We have selected three informative SNPs (rs762855, rs3856973 and rs4690073) to study these haplogroups in an Indian sample. Our results show that the genotype frequencies are significantly different between cases and controls for these SNPs. More than 90% of both cases and controls belong to Haplogroup A which is the predominant European haplogroup.

scholarly journals The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

2021 ◽  
Vol 14 (3) ◽  
pp. 257
Author(s):  
Elisabeth Singer ◽  
Lilit Hunanyan ◽  
Magda M. Melkonyan ◽  
Jonasz J. Weber ◽  
Lusine Danielyan ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Model ◽  
Resonance Energy Transfer ◽  
Neuronal Cell ◽  
Resonance Energy ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Cell Models

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.

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