Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.

The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals.

Patient-specific responses to splice-modifying treatments in spinal muscular atrophy fibroblasts.

The availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing of , but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions among SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients.

Altered mitochondrial function in fibroblast cell lines derived from disease carriers of spinal muscular atrophy.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive childhood-onset neuromuscular disease with a carrier frequency of ~1:50. Mitochondrial abnormalities are widespread in patients with SMA. Disease carriers for SMA (i.

Prevalence, clinical presentation, and etiology of myelopathies in 224 juvenile dogs.

Background: Intervertebral disc herniation is widely recognized as the most common cause of myelopathy in dogs older than 2 years; however, the prevalence of various causes of myelopathy in younger dogs has not been reported.

Hypothesis/objectives: To describe the prevalence, clinical presentation, and etiology of myelopathy in dogs aged 18 months or less. Secondarily, to investigate which clinical features were associated with each of the most common etiologies.

Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.

Aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43 mice.

A TNR Frameshift Variant in Weimaraner Dogs with an Exercise-Induced Paroxysmal Movement Disorder.

Background: Some paroxysmal movement disorders remain without an identified genetic cause.

Objectives: The aim was to identify the causal genetic variant for a paroxysmal dystonia-ataxia syndrome in Weimaraner dogs.

Methods: Clinical and diagnostic investigations were performed.

SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain.

Background: Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers.

Objectives: To clinically and genetically characterize CIP in a family of mixed breed dogs.

Otitis media and interna with or without polyps in cats: association between meningeal enhancement on postcontrast MRI, cerebrospinal fluid abnormalities, and clinician treatment choice and outcome.

Objectives: The aim of this study was to evaluate the association between meningeal enhancement (MgE) and cerebrospinal fluid (CSF) analysis results, their individual association with bacteriology results from affected ear samples and whether these test results influenced clinicians' therapeutic choice in cats with otitis media and interna (OMI).

Methods: This was a multicentre retrospective study carried out over an 8-year period. Cats diagnosed with OMI, with or without a nasopharyngeal polyp, leading to peripheral vestibular signs were included.

Design and fabrication of a stereo-video camera equipped unoccupied aerial vehicle for measuring sea turtles, sharks, and other marine fauna.

The recent commercialization of unoccupied aerial vehicles (UAVs) has facilitated their incorporation into a variety of ecological studies. While UAVs are able to provide accurate visual data of marine species from an aerial perspective, these devices have some limitations that make measuring marine animals below the surface challenging. Many marine organisms are often visible from the air, but are deeper in the water column, and current methods cannot measure animals below the surface.

Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.

Methods: Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS.

Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine.

Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease that, in the most severe cases and when left untreated, leads to death within the first two years of life. Recent therapeutic advances have given hope to families and patients by compensating for the deficiency in survival motor neuron (SMN) protein via gene therapy or other genetic manipulation. However, it is now apparent that none of these therapies will cure SMA alone.

Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of whether SMA has presymptomatic, developmental components to disease pathogenesis.

Renal pathology in a mouse model of severe Spinal Muscular Atrophy is associated with downregulation of Glial Cell-Line Derived Neurotrophic Factor (GDNF).

Spinal muscular atrophy (SMA) occurs as a result of cell-ubiquitous depletion of the essential survival motor neuron (SMN) protein. Characteristic disease pathology is driven by a particular vulnerability of the ventral motor neurons of the spinal cord to decreased SMN. Perhaps not surprisingly, many other organ systems are also impacted by SMN depletion.

Variation in the position of the conus medullaris and dural sac in adult dogs.

Although it has long been stated that the level of spinal cord termination varies depending on the size of the dog, the evidence for this remains limited. The aim of this study is to investigate the position of the conus medullaris (CM) and dural sac (DS) in a population of dogs of varying size. MRIs of the thoracolumbosacral spine of 101 dogs were included.

The role of survival motor neuron protein (SMN) in protein homeostasis.

Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy.

An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides.

Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine.

Aims: Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis.

Proof of concept and feasibility studies examining the influence of combination ribose, adenine and allopurinol treatment on stroke outcome in the rat.

Background: Cerebral ischaemia results in a rapid and profound depletion of adenosine triphosphate (ATP), the energy currency of the cell. This depletion leads to disruption of cellular homeostasis and cell death. Early replenishment of ATP levels might therefore have a neuroprotective effect in the injured brain.