Housing R6/2 Mice with Wild-Type Littermates Increases Lifespan

2021 ◽  
pp. 1-4
Author(s):  
Darren Story ◽  
John Gallien ◽  
Abeer Al-Gharaibeh ◽  
Michael Sandstrom ◽  
Julien Rossignol ◽  
...  
Keyword(s):  
Weight Loss ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Murine Model ◽  
Standard Diet ◽  
Wild Type ◽  
The Impact

The R6/2 murine model of Huntington’s disease (HD) is extensively used in HD research. The current study replicates and extends previous work assessing the impact of housing R6/2 mice with healthy wild-type (WT) littermates on disease progression. The current study extends the previous finding by including male cohorts and the use of a standard diet and water regimen, as opposed to the enhanced diet used in the previous study. This study found that the inclusion of healthy wild-type (WT) littermates, alone, improved survivabilty in R6/2 mice, but did not have a significant impact on weight loss.

Abnormal Spinal Cord Myelination due to Oligodendrocyte Dysfunction in a Model of Huntington’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Costanza Ferrari Bardile ◽  
Harwin Sidik ◽  
Reynard Quek ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Marta Garcia-Miralles ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Oligodendrocyte Progenitor Cells ◽  
Wild Type ◽  
Specific Expression ◽  
Relative Contribution ◽  
Related Proteins ◽  
The Impact ◽  
Cervical Area

Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods: Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results: We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion: Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities.

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

scholarly journals Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington's disease progression

2021 ◽  
Vol 186 ◽  
pp. 108467
Author(s):  
Simon Couly ◽  
Allison Carles ◽  
Morgane Denus ◽  
Lorraine Benigno-Anton ◽  
Florence Maschat ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Enriched Environment ◽  
Therapy Efficacy

scholarly journals Characterising Upper Limb Movements in Huntington's Disease and the Impact of Restricted Visual Cues

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0133709 ◽  
Author(s):  
Jessica Despard ◽  
Anne-Marie Ternes ◽  
Bleydy Dimech-Betancourt ◽  
Govinda Poudel ◽  
Andrew Churchyard ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Upper Limb ◽  
Visual Cues ◽  
Limb Movements ◽  
Upper Limb Movements ◽  
The Impact

scholarly journals Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

2021 ◽  
Vol 13 ◽  
Author(s):  
Maria Iuliano ◽  
Connor Seeley ◽  
Ellen Sapp ◽  
Erin L. Jones ◽  
Callie Martin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Plasma Membranes ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Synaptic Membrane ◽  
Wild Type ◽  
Functional Changes ◽  
Mouse Striatum ◽  
Old Mice

Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington’s disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.

scholarly journals The relationship between non-motor features and weight-loss in the premanifest stage of Huntington’s disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253817
Author(s):  
Wasiq Khan ◽  
Sundus Alusi ◽  
Hissam Tawfik ◽  
Abir Hussain
Keyword(s):  
Weight Loss ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Expert Knowledge ◽  
Strong Association ◽  
Machine Intelligence ◽  
Rule Mining ◽  
First Time ◽  
The Relationship ◽  
Relevant Factors

Weight-loss is an integral part of Huntington’s disease (HD) that can start before the onset of motor symptoms. Investigating the underlying pathological processes may help in the understanding of this devastating disease as well as contribute to its management. However, the complex behavior and associations of multiple biological factors is impractical to be interpreted by the conventional statistics or human experts. For the first time, we combine a clinical dataset, expert knowledge and machine intelligence to model the multi-dimensional associations between the potentially relevant factors and weight-loss activity in HD, specifically at the premanifest stage. The HD dataset is standardized and transformed into required knowledge base with the help of clinical HD experts, which is then processed by the class rule mining and self-organising maps to identify the significant associations. Statistical results and experts’ report indicate a strong association between severe weight-loss in HD at the premanifest stage and measures of certain cognitive, psychiatric functional ability factors. These results suggest that the mechanism underlying weight-loss in HD is, at least partly related to dysfunction of certain areas of the brain, a finding that may have not been apparent otherwise. These associations will aid the understanding of the pathophysiology of the disease and its progression and may in turn help in HD treatment trials.

scholarly journals The impact of the gut microbiota on Huntington's disease mice

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S370-S371
Author(s):  
Carolina De Moura Gubert ◽  
Geraldine Kong ◽  
Jamie Liew ◽  
Chloe Love ◽  
Thibault Renoir ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
The Impact

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.

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