scholarly journals ABHD6 inhibition rescues a sex-dependent deficit in motor coordination in the HdhQ200/200 mouse model of Huntington’s disease

2021 ◽  
Author(s):  
Jessica K. Cao ◽  
Katie Viray ◽  
Myungsun Shin ◽  
Ku-Lung Hsu ◽  
Ken Mackie ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Coordination ◽  
Motor Behavior ◽  
Wild Type ◽  
Severe Phenotype ◽  
Behavioral Deficits ◽  
Immunohistochemistry Analysis ◽  
Pump Delivery ◽  
Preliminary Study

Abstract Huntington’s Disease is associated with motor behavior deficits that current therapeutics do not alleviate. This pilot study tested if pharmacological inhibition of a/b-hydrolase domain containing 6 (ABHD6), a multifunctional enzyme expressed in the striatum, rescues behavioral deficits in HdhQ200/200 mice. Previous work has shown that this model exhibits a reduction in spontaneous locomotion and motor coordination at 8 and 10 months of age, with a more severe phenotype in female mice. Semi-quantitative immunohistochemistry analysis indicated no change in striatal ABHD6 expression at 8 months of age, but a 40% reduction by 10 months in female HdhQ200/200 mice compared to female wild-type (WT) littermates. At 8 months of age, acute ABHD6 inhibition selectively rescued motor coordination deficits in female HdhQ200/200 mice without affecting WT performance. ABHD6 inhibition did not impact spontaneous locomotion, grip strength or overall weight in either group, showing that effects were specific to motor coordination. At 10 months of age, semi-chronic ABHD6 inhibition by osmotic pump delivery also rescued motor coordination deficits in female HdhQ200/200 mice without affecting female WT littermates. Our preliminary study suggests that ABHD6 inhibition selectively improves motor performance in female HdhQ200/200 mice.

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.

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 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 Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

2021 ◽  
Author(s):  
Sandra M. Holley ◽  
Jack C. Reidling ◽  
Carlos Cepeda ◽  
Alice Lau ◽  
Cindy Moore ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pyramidal Neurons ◽  
Neurodegenerative Disorder ◽  
Functional Integration ◽  
Behavioral Deficits ◽  
Human Neural Stem Cells ◽  
Neuronal Populations

AbstractHuntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

scholarly journals EGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington’s Disease

2019 ◽  
Vol 56 (11) ◽  
pp. 7708-7718 ◽  
Author(s):  
Felecia M. Marottoli ◽  
Mercedes Priego ◽  
Eden Flores-Barrera ◽  
Rohan Pisharody ◽  
Steve Zaldua ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Behavior ◽  
Gabaergic Function

scholarly journals Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1514 ◽  
Author(s):  
Aleksandra S. Taran ◽  
Lilia D. Shuvalova ◽  
Maria A. Lagarkova ◽  
Irina B. Alieva
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Autosomal Dominant ◽  
Cell Physiology ◽  
Mutant Form ◽  
Striatal Neurons ◽  
Molecular Processes ◽  
Wild Type ◽  
Cellular Processes ◽  
Cell Structures

Huntington’s disease is a severe and currently incurable neurodegenerative disease. An autosomal dominant mutation in the Huntingtin gene (HTT) causes an increase in the polyglutamine fragment length at the protein N-terminus. The consequence of the mutation is the death of neurons, mostly striatal neurons, leading to the occurrence of a complex of motor, cognitive and emotional-volitional personality sphere disorders in carriers. Despite intensive studies, the functions of both mutant and wild-type huntingtin remain poorly understood. Surprisingly, there is the selective effect of the mutant form of HTT even on nervous tissue, whereas the protein is expressed ubiquitously. Huntingtin plays a role in cell physiology and affects cell transport, endocytosis, protein degradation and other cellular and molecular processes. Our experimental data mining let us conclude that a significant part of the Huntingtin-involved cellular processes is mediated by microtubules and other cytoskeletal cell structures. The review attempts to look at unresolved issues in the study of the huntingtin and its mutant form, including their functions affecting microtubules and other components of the cell cytoskeleton.

scholarly journals Abnormalities in the Motor Unit of a Fast-Twitch Lower Limb Skeletal Muscle in Huntington’s Disease

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141988621 ◽  
Author(s):  
Priscila Aparecida Costa Valadão ◽  
Bárbara Campos de Aragão ◽  
Jéssica Neves Andrade ◽  
Matheus Proença S. Magalhães-Gomes ◽  
Giselle Foureaux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Tibialis Anterior ◽  
Neuromuscular Junctions ◽  
Motor Behavior ◽  
Psychiatric Symptoms ◽  
Artificial Chromosome ◽  
Ultrastructural Level ◽  
Fast Twitch

Huntington’s disease (HD) is a disorder characterized by chronic involuntary movements, dementia, and psychiatric symptoms. It is caused by a mutation in the gene that encodes for huntingtin protein (HTT), leading to the formation of mutant proteins expressed in various tissues. Although brain pathology has become the hallmark for HD, recent studies suggest that damage of peripheral structures also contributes to HD progression. We previously identified severe alterations in the motor units that innervate cervical muscles in 12-month-old BACHD (Bacterial Artificial Chromosome Huntington’s Disease) mice, a well-established mouse model for HD. Here, we studied lumbar motoneurons and their projections onto hind limb fast-twitch skeletal muscles (tibialis anterior), which control balance and gait in HD patients. We found that lumbar motoneurons were altered in the HD mouse model; the number and size of lumbar motoneurons were reduced in BACHD. Structural alterations were also present in the sciatic nerve and neuromuscular junctions. Acetylcholine receptors were organized in several small patches (acetylcholine receptor fragmentation), many of which were partially innervated. In BACHD mice, we observed atrophy of tibialis anterior muscles, decreased expression of glycolytic fast Type IIB fibers, and at the ultrastructural level, alterations of sarcomeres and mitochondria. Corroborating all these findings, BACHD animals performed worse on motor behavior tests. Our results provide additional evidences that nerve–muscle communication is impaired in HD and that motoneurons from distinct spinal cord locations are similarly affected in the disease.

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