Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.

Huntington's disease (HD) arises from a CAG expansion in the () gene beyond a critical threshold. A major thrust of current HD therapeutic development is lowering levels of mutant mRNA (m) and protein (mHTT) with the aim of reducing the toxicity of these product(s). Human genetic data also support a key role for somatic instability (SI) in 's CAG repeat - whereby it lengthens with age in specific somatic cell types - as a key driver of age of motor dysfunction onset.

Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT) that results in toxic gain of function and cell death. Despite its monogenic cause, the pathogenesis of HD is highly complex, and increasing evidence indicates that, in addition to the full-length (FL) mutant HTT protein, the expanded exon 1 HTT (HTTexon1) protein that is translated from the HTT1a transcript generated by aberrant splicing is prone to aggregate and might contribute to HD pathology. This finding suggests that reducing the expression of HTT1a might achieve a greater therapeutic benefit than targeting only FL mutant HTT.

Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG tract in the huntingtin (HTT) gene, leading to toxic gains of function. HTT-lowering treatments are in clinical trials, but the risks imposed are unclear. Recent studies have reported on the consequences of widespread HTT loss in mice, where one group described early HTT loss leading to fatal pancreatitis, but later loss as benign.

Dysphagia as a Missing Link Between Post-surgical- and Opioid-Related Pneumonia.

Purpose: Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk.

Methods: Eight healthy adult cats were evaluated to determine changes in airway protection status and for evidence of dysphagia in two experiments.

An evaluation of the effectiveness of an advanced practice physiotherapist in the emergency department setting in Ireland.

Background: One of the means of easing increased pressure on emergency care worldwide has been the development of advanced musculoskeletal physiotherapy practice in the emergency department setting. This model of care is in its infancy in Ireland.

Aims: To evaluate the effectiveness of an advanced practice physiotherapist working as a primary contact clinician in the emergency department at St.

Levels of Synaptic Proteins in Brain and Neurofilament Light Chain in Cerebrospinal Fluid and Plasma of OVT73 Huntington's Disease Sheep Support a Prodromal Disease State.

Background: Synaptic changes occur early in patients with Huntington's disease (HD) and in mouse models of HD. An analysis of synaptic changes in HD transgenic sheep (OVT73) is fitting since they have been shown to have some phenotypes. They also have larger brains, longer lifespan, and greater motor and cognitive capacities more aligned with humans, and can provide abundant biofluids for in vivo monitoring of therapeutic interventions.

Huntingtin loss in hepatocytes is associated with altered metabolism, adhesion, and liver zonation.

Huntington's disease arises from a toxic gain of function in the ( ) gene. As a result, many HTT-lowering therapies are being pursued in clinical studies, including those that reduce HTT RNA and protein expression in the liver. To investigate potential impacts, we characterized molecular, cellular, and metabolic impacts of chronic HTT lowering in mouse hepatocytes.

SmartPill™ Administration to Assess Gastrointestinal Function after Spinal Cord Injury in a Porcine Model-A Preliminary Study.

Gastrointestinal (GI) complications, including motility disorders, metabolic deficiencies, and changes in gut microbiota following spinal cord injury (SCI), are associated with poor outcomes. After SCI, the autonomic nervous system becomes unbalanced below the level of injury and can lead to severe GI dysfunction. The SmartPill™ is a non-invasive capsule that, when ingested, transmits pH, temperature, and pressure readings that can be used to assess effects in GI function post-injury.

Recovery of walking in nonambulatory children with chronic spinal cord injuries: Case series.

The immature central nervous system is recognized as having substantial neuroplastic capacity. In this study, we explored the hypothesis that rehabilitation can exploit that potential and elicit reciprocal walking in nonambulatory children with chronic, severe (i.e.

Porcine spinal cord injury model for translational research across multiple functional systems.

Animal models are necessary to identify pathological changes and help assess therapeutic outcomes following spinal cord injury (SCI). Small animal models offer value in research in terms of their easily managed size, minimal maintenance requirements, lower cost, well-characterized genomes, and ability to power research studies. However, despite these benefits, small animal models have neurologic and anatomical differences that may influence translation of results to humans and thus limiting the success of their use in preclinical studies as a direct pipeline to clinical studies.

Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model.

We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically.

Laryngeal and swallow dysregulation following acute cervical spinal cord injury.

Laryngeal function is vital to airway protection. Although swallow is mediated by the brainstem, the mechanism underlying the increased risk of dysphagia after cervical spinal cord injury (SCI) is unknown. We hypothesized that: ) loss of descending phrenic drive affects swallow and breathing differently, and ) loss of ascending spinal afferent information alters swallow regulation.

Non-uniform upregulation of the autogenic stretch reflex among hindlimb extensors following lateral spinal lesion in the cat.

Successful propagation throughout the step cycle is contingent on adequate regulation of whole-limb stiffness by proprioceptive feedback. Following spinal cord injury (SCI), there are changes in the strength and organization of proprioceptive feedback that can result in altered joint stiffness. In this study, we measured changes in autogenic feedback of five hindlimb extensor muscles following chronic low thoracic lateral hemisection (LSH) in decerebrate cats.

Development of novel bioassays to detect soluble and aggregated Huntingtin proteins on three technology platforms.

Huntington's disease is caused by a CAG / polyglutamine repeat expansion. Mutated CAG repeats undergo somatic instability, resulting in tracts of several hundred CAGs in the brain; and genetic modifiers of Huntington's disease have indicated that somatic instability is a major driver of age of onset and disease progression. As the CAG repeat expands, the likelihood that exon 1 does not splice to exon 2 increases, resulting in two transcripts that encode full-length huntingtin protein, as well as the highly pathogenic and aggregation-prone exon 1 huntingtin protein.

Characterization of Lower Urinary Tract Dysfunction after Thoracic Spinal Cord Injury in Yucatan Minipigs.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI.

Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.

Huntington's disease pathogenesis involves a genetic gain-of-function toxicity mechanism triggered by the expanded HTT CAG repeat. Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin's normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated a rare family segregating two presumed HTT loss-of-function (LoF) variants associated with the developmental disorder, Lopes-Maciel-Rodan syndrome (LOMARS), using whole-genome sequencing of DNA from cell lines, in conjunction with analysis of mRNA and protein expression.

Large Animal Models of Huntington's Disease: What We Have Learned and Where We Need to Go Next.

Genetically modified rodent models of Huntington's disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully recapitulate human disease features or adequately predict a clinical response to treatment. Therefore, conducting translational studies of candidate HD therapeutics only in a single species (i.

Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington's disease knock-in mice is blocked by Mlh1 knock-out.

Recent genome-wide association studies of age-at-onset in Huntington's disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability.

Treadmill-Based Gait Kinematics in the Yucatan Mini Pig.

Yucatan miniature pigs (YMPs) are similar to humans in spinal cord size as well as physiological and neuroanatomical features, making them a useful model for human spinal cord injury. However, little is known regarding pig gait kinematics, especially on a treadmill. In this study, 12 healthy YMPs were assessed during bipedal and/or quadrupedal stepping on a treadmill at six speeds (1.

Sex-specific vagal and spinal modulation of breathing with chest compression.

Lung volume is modulated by sensory afferent feedback via vagal and spinal pathways. The purpose of this study was to systematically alter afferent feedback with and without a mechanical challenge (chest compression). We hypothesized that manipulation of afferent feedback by nebulization of lidocaine, extra-thoracic vagotomy, or lidocaine administration to the pleural space would produce differential effects on the motor pattern of breathing during chest compression in sodium pentobarbital anesthetized rats (N = 43).

Redistribution of inhibitory force feedback between a long toe flexor and the major ankle extensor muscles following spinal cord injury.

Inhibitory pathways from Golgi tendon organs project widely between muscles crossing different joints and axes of rotation. Evidence suggests that the strength and distribution of this intermuscular inhibition is dependent on motor task and corresponding signals from the brainstem. The purpose of the present study was to investigate whether this sensory network is altered after spinal cord hemisection as a potential explanation for motor deficits observed after spinal cord injury (SCI).

Sex-specific vagal and spinal modulation of swallow and its coordination with breathing.

Swallow-breathing coordination is influenced by changes in lung volume, which is modulated by feedback from both vagal and spinal sensory afferents. The purpose of this study was to manipulate feedback from these afferents, with and without a simultaneous mechanical challenge (chest compression), in order to assess the influence of each sensory pathway on swallow in rats. We hypothesized that manipulation of afferent feedback would shift the occurrence of swallow toward the inspiratory phase of breathing.