HDinHD: A Rich Data Portal for Huntington’s Disease Research

2021 ◽  
pp. 1-8
Author(s):  
Jeff Aaronson ◽  
Vahri Beaumont ◽  
Richard A. Blevins ◽  
Viktoria Andreeva ◽  
Irina Murasheva ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Scientific Data ◽  
High Definition ◽  
Related Data ◽  
Online Portal ◽  
Wide Range ◽  
Data Portal ◽  
Rich Data

HDinHD (Huntington’s Disease in High Definition; HDinHD.org) is an open online portal for the HD research community that presents a synthesized view of HD-related scientific data. Here, we present a broad overview of HDinHD and highlight the newly launched HDinHD Explorer tool that enables researchers to discover and explore a wide range of diverse yet interconnected HD-related data. We demonstrate the utility of HDinHD Explorer through data mining of a single collection of newly released in vivo therapeutic intervention study reports alongside previously published reports.

scholarly journals A System-Agnostic, Adaptable and Extensible Animal Support Cradle System for Cardio-Respiratory-Synchronised, and Other, Multi-Modal Imaging of Small Animals

Tomography ◽  
2021 ◽  
Vol 7 (1) ◽  
pp. 39-54
Author(s):  
Veerle Kersemans ◽  
Stuart Gilchrist ◽  
Philip Danny Allen ◽  
Sheena Wallington ◽  
Paul Kinchesh ◽  
...  
Keyword(s):  
Scientific Data ◽  
Cardiac Monitoring ◽  
Small Animals ◽  
Maintenance System ◽  
Wide Range ◽  
Set Up ◽  
Animal Handling ◽  
Imaging Performance ◽  
Significant Effort

Standardisation of animal handling procedures for a wide range of preclinical imaging scanners will improve imaging performance and reproducibility of scientific data. Whilst there has been significant effort in defining how well scanners should operate and how in vivo experimentation should be practised, there is little detail on how to achieve optimal scanner performance with best practices in animal welfare. Here, we describe a system-agnostic, adaptable and extensible animal support cradle system for cardio-respiratory-synchronised, and other, multi-modal imaging of small animals. The animal support cradle can be adapted on a per application basis and features integrated tubing for anaesthetic and tracer delivery, an electrically driven rectal temperature maintenance system and respiratory and cardiac monitoring. Through a combination of careful material and device selection, we have described an approach that allows animals to be transferred whilst under general anaesthesia between any of the tomographic scanners we currently or have previously operated. The set-up is minimally invasive, cheap and easy to implement and for multi-modal, multi-vendor imaging of small animals.

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.

In vivo examination of the Pre- and postsynaptic dopamine neurons in huntington's disease

1996 ◽  
Vol 6 ◽  
pp. 130
Author(s):  
N. Ginovart ◽  
A. Lundin ◽  
L. Farde ◽  
C. Halldin ◽  
C.G. Swahn ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Dopamine Neurons

scholarly journals Cortical circuit alterations precede disease onset in Huntington’s disease mice

2018 ◽  
Author(s):  
Johanna Neuner ◽  
Elena Katharina Schulz-Trieglaff ◽  
Sara Gutiérrez-Ángel ◽  
Fabian Hosp ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Primary Motor Cortex ◽  
Disease Onset ◽  
Single Neurons ◽  
Two Photon ◽  
Layer 2 ◽  
Cortical Circuit

AbstractHuntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

scholarly journals Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
P. Stepanova ◽  
V. Srinivasan ◽  
D. Lindholm ◽  
M. H. Voutilainen
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Quinolinic Acid ◽  
Neurotrophic Factor ◽  
Striatal Neurons ◽  
In Vivo Models ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
Cerebral Dopamine

Abstract Huntington’s disease (HD) is a neurodegenerative disorder with a progressive loss of medium spiny neurons in the striatum and aggregation of mutant huntingtin in the striatal and cortical neurons. Currently, there are no rational therapies for the treatment of the disease. Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) properties, protecting and restoring the function of dopaminergic neurons in animal models of PD more effectively than other NTFs. CDNF is currently in phase I–II clinical trials on PD patients. Here we have studied whether CDNF has beneficial effects on striatal neurons in in vitro and in vivo models of HD. CDNF was able to protect striatal neurons from quinolinic acid (QA)-induced cell death in vitro via increasing the IRE1α/XBP1 signalling pathway in the ER. A single intrastriatal CDNF injection protected against the deleterious effects of QA in a rat model of HD. CDNF improved motor coordination and decreased ataxia in QA-toxin treated rats, and stimulated the neurogenesis by increasing doublecortin (DCX)-positive and NeuN-positive cells in the striatum. These results show that CDNF positively affects striatal neuron viability reduced by QA and signifies CDNF as a promising drug candidate for the treatment of HD.

scholarly journals Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

2019 ◽  
Vol 100 (2) ◽  
pp. 64-71
Author(s):  
Olga A. Zhunina ◽  
Nikita G. Yabbarov ◽  
Alexander N. Orekhov ◽  
Alexey V. Deykin
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease

scholarly journals IKKβ slows Huntington’s disease progression in R6/1 mice

2019 ◽  
Vol 116 (22) ◽  
pp. 10952-10961 ◽  
Author(s):  
Joseph Ochaba ◽  
Gianna Fote ◽  
Marketta Kachemov ◽  
Soe Thein ◽  
Sylvia Y. Yeung ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Degeneration ◽  
Neuronal Injury ◽  
Therapeutic Interventions ◽  
Striatal Neurons ◽  
Microglial Response ◽  
Relationship Of ◽  
The Impact

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

scholarly journals Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington’s Disease: a Longitudinal PET Study

2020 ◽  
Vol 57 (4) ◽  
pp. 2038-2047 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Špela Korat ◽  
Alan Miranda ◽  
Klaudia Cybulska ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Post Mortem ◽  
Metabotropic Glutamate ◽  
Group I

AbstractImpairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington’s Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [11C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [11C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [11C]ITDM PET imaging demonstrated higher [11C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

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