Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS

Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1G93A allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices

Characterization of amyloid-\u3b2 deposits in bovine brains

Amyloid-\u3b2 (A\u3b2) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes A\u3b2 deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular A\u3b2 deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain A\u3b2 deposits, indicating the non \u3b2-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different A\u3b2 peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between A\u3b2 deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same A\u3b2 peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation

Whole blood gene expression profiling in preclinical and clinical cattle infected with atypical bovine spongiform encephalopathy

Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named Hand L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSEinfected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. \ua9 2016 Xerxa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Novel transgenic animal model of Amyotrophic Lateral Sclerosis

The present invention concerns a novel transgenic animal as model of Amyotrophic Lateral Sclerosis (ALS)

Canine adenovirus type 1 and Pasteurella pneumotropica co–infection in a puppy [Co‑infezione di adenovirus canino tipo 1 e Pasteurella pneumotropica in un cucciolo di pastore tedesco]

In 2008, a 2‑month‑old male German shepherd was presented with fever, depression, and evident organic wasting. The puppy died within 48 hours after the onset of clinical signs. A complete necropsy was performed. Bacteriological examination of samples from the brain, lung, liver, spleen, and bone marrow tested positive for Pasteurella pneumotropica. Histopathology demonstrated inflammatory and vascular lesions in the central nervous system and internal organs. Canine adenovirus type 1 (CAdV‑1) nucleic acid was detected by polymerase chain reaction (PCR) in the frozen brain but not in the formalin‑fixed, paraffin‑embedded liver and lung samples. The positive PCR was subsequently confirmed by indirect fluorescent antibody testing of the paraffin‑embedded brain and liver sections. Although the liver is the primary site of viral damage, these laboratory findings suggest that CAdV‑1 infection should be included in the differential diagnosis of neuropathological diseases in dogs and that adenoviral infections could promote septicaemia caused by opportunistic pathogens

Gene enrichment analysis of DEGs specific of the clinical and preclinical stage of the disease.

<p>The most relevant GO terms (y axis) associated to clinical (<b>A</b>) and preclinical (<b>B</b>) phase are listed according to decreasing statistical significance from top to bottom. The threshold for statistical significance is marked by the green lines. The enrichment analysis was performed using DAVID bioinformatics tool 6.7 (NIAID/NIH, USA).</p

Heat maps representing the DEGs found in clinical and preclinical cattle with atypical BSE.

<p>Two heat maps were generated using the <i>heatmap</i>.<i>2</i> function from the <i>gplots</i> library in <i>R</i> statistical environment. DEGs were hierarchically clustered with complete linkage using the Euclidean metric. The heat maps represent the most significant DEGs (p value ≤.0.05 and fold change ≥ 2) in clinical (A) and preclinical (B) animals compared to the control group. Animals are reported in the x-axis while the differentially expressed probes are in the y-axis.</p

List of DEGs characterized by an up-down/down-up pattern of expression.^a

<p>List of DEGs characterized by an up-down/down-up pattern of expression.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153425#t003fn001" target="_blank">^a</a></p

Functional classification of differentially expressed genes in blood of infected cattle versus control group^a.

<p>Functional classification of differentially expressed genes in blood of infected cattle versus control group<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153425#t002fn001" target="_blank">^a</a>.</p