Ataxin-3, The Spinocerebellar Ataxia Type 3 Neurodegenerative Disorder Protein, Affects Mast Cell Functions.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is a progressive neurodegenerative disorder characterized by loss of neuronal matter due to the expansion of the CAG repeat in the gene and subsequent ataxin-3 protein. Although the underlying pathogenic protein expansion has been known for more than 20 years, the complexity of its effects is still under exploration. The ataxin-3 protein in its expanded form is known to aggregate and disrupt cellular processes in neuronal tissue but the role of the protein on populations of immune cells is unknown.

A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes.

Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms.

Detecting and Quantifying Ataxia-Related Motor Impairments in Rodents Using Markerless Motion Tracking With Deep Neural Networks.

In this study we evaluate the application of video-based markerless motion tracking based on deep neural networks for the analysis of ataxia-specific movement abnormalities in rodent models of cerebellar ataxia. Based on a small amount (<100) of manually labeled video frames, markerless motion tracking enabled the extraction of movement trajectories and parameters characterizing ataxia-specific movement abnormalities. In the first experiment, we analyzed videos of 6 shaker and 4 wildtype rats and were able to reproduce thê5 Hz tremor frequency in the shaker rat without the usage of a force plate.

Increased expression of myelin-associated genes in frontal cortex of overexpressing rats and Parkinson's disease patients.

Parkinson's disease (PD) is an age-dependent neurodegenerative disorder. Besides characteristic motor symptoms, patients suffer from cognitive impairments linked to pathology in cortical areas. Due to obvious challenges in tracing the underlying molecular perturbations in human brain over time, we took advantage of a well-characterized PD rat model.

Commissioning, dosimetric characterization and machine performance assessment of the LIAC HWL mobile accelerator for Intraoperative Radiotherapy.

Background: The LIAC HWL (Sordina IORT Technologies, Vicenza, Italy) is a recently designed mobile linear accelerator for intraoperative electron radiotherapy (IOeRT), producing high dose rate electron beams at four different energy levels. It features a software tool for the visualization of 2D dose distributions, which is based on Monte Carlo simulations. The aims of this work were to (i) assess the dosimetric characteristics of the accelerator, (ii) experimentally verify calculated data exported from the software and (iii) report on commissioning as well as performance of the system during the first year of operation.

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice.

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH.

Calpain-1 ablation partially rescues disease-associated hallmarks in models of Machado-Joseph disease.

Proteolytic fragmentation of polyglutamine-expanded ataxin-3 is a concomitant and modifier of the molecular pathogenesis of Machado-Joseph disease (MJD), the most common autosomal dominant cerebellar ataxia. Calpains, a group of calcium-dependent cysteine proteases, are important mediators of ataxin-3 cleavage and implicated in multiple neurodegenerative conditions. Pharmacologic and genetic approaches lowering calpain activity showed beneficial effects on molecular and behavioural disease characteristics in MJD model organisms.

Development of an AAV-Based MicroRNA Gene Therapy to Treat Machado-Joseph Disease.

Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by a CAG expansion in the gene. The expanded CAG repeat is translated into a prolonged polyglutamine repeat in the ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results in degeneration of the cerebellum and brain stem. In the current study, a non-allele-specific silencing approach was investigated using artificial microRNAs engineered to target various regions of the gene (miATXN3).

Embedding DNA in surfactant mesophases: the phase diagram of the ternary system dodecyltrimethylammonium-DNA/monoolein/water in comparison to the DNA-free analogue.

The self-assembly of a true ternary mixture comprising an electroneutral complex of DNA anions and surfactant cations (dodecyltrimethylammonium cations, DTA), water, and nonionic surfactant (monoolein, MO) has been studied. The phase diagrams of two systems, DTA-DNA/MO/water and, for comparison, dodecyltrimethylammonium bromide (DTAB)/MO/water, were obtained by visual inspection, microscopic examination under polarized light, small-angle X-ray scattering (SAXS) and deuterium NMR ((2)H NMR) at 298 K and normal pressure. The isothermal phase diagram of the DTA-DNA/MO/water system contains four liquid crystalline (LC) phase regions (reversed hexagonal, Pn3m, Ia3d, lamellar).