Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.
Background: Hereditary cerebellar degeneration is described in several dog breeds. This heterogeneous group of diseases causes cerebellar ataxia associated with cerebellar cortical degeneration.Objective: To report the clinical and histopathological features, and describe the mode of inheritance of hereditary cerebellar degeneration in Scottish Terriers.Animals: Sixty-two affected dogs recruited through the Scottish Terrier Club of America. Materials and Methods: Prospective, observational study: Owners of affected dogs were contacted for a description of clinical signs, age of onset, and disease progression. Medical records, videotapes of gait, and brain imaging were evaluated. When possible, necropsy was performed and the brain examined histopathologically. Prevalence of the disease was estimated and a pedigree analysis was performed to determine mode of inheritance.Results: Gait abnormalities were noted in the 1st year of life in 76% of dogs, and progressed slowly; only 1 of 27 dogs dead at time of writing was euthanized because of cerebellar degeneration. Clinical signs included wide based stance, dysmetria, intention tremor, and difficulty negotiating stairs and running. Cerebellar atrophy was detected on magnetic resonance imaging. On histopathological examination, there was segmental loss of Purkinje neurons, thinning of molecular and granular layers, and polyglucosan bodies in the molecular layer. Prevalence of disease was estimated at 1 in 1,335 American Kennel Club registered Scottish Terriers. Genetic analysis results are consistent with an autosomal recessive mode of inheritance.Conclusion and Clinical Importance: A hereditary cerebellar degenerative disorder with a relatively mild phenotype has emerged in the Scottish Terrier. Genetic studies are needed.
Adequate bony support is the key to re-establish both function and esthetics in the craniofacial region. Autologous bone grafting has been the gold standard for regeneration of problematic large bone defects. However, poor graft availability and donor-site complications have led to alternative bone tissue-engineering approaches combining osteoinductive biomaterials and three-dimensional cell aggregates in scaffolds or constructs. The goal of the present study was to generate novel cell aggregate-loaded macroporous scaffolds combining the osteoinductive properties of titanium dioxide (TiO 2 ) with hydroxyapatite-gelatin nanocomposites (HAP-GEL) for regeneration of craniofacial defects. Here we investigated the in vivo applicability of macroporous (TiO 2 )-enriched HAP-GEL scaffolds with undifferentiated and osteogenically differentiated multipotent adult progenitor cell (MAPC and OD-MAPC, respectively) aggregates for calvaria bone regeneration. The silane-coated HAP-GEL with and without TiO 2 additives were polymerized and molded to produce macroporous scaffolds. Aggregates of the rat MAPC were precultured, loaded into each scaffold, and implanted to rat calvaria criticalsize defects to study bone regeneration. Bone autografts were used as positive controls and a poly(lacticco-glycolic acid) (PLGA) scaffold for comparison purposes. Preimplanted scaffolds and calvaria bone from pig were tested for ultimate compressive strength with an Instron 4411 Ò and for porosity with microcomputerized tomography (mCT). Osteointegration and newly formed bone (NFB) were assessed by mCT and nondecalcified histology, and quantified by calcium fluorescence labeling. Results showed that the macroporous TiO 2 -HAP-GEL scaffold had a comparable strength relative to the natural calvaria bone (13.8 -4.5 MPa and 24.5 -8.3 MPa, respectively). Porosity was 1.52 -0.8 mm and 0.64 -0.4 mm for TiO 2 -HAP-GEL and calvaria bone, respectively. At 8 and 12 weeks postimplantation into rat calvaria defects, greater osteointegration and NFB were significantly present in the TiO 2 -enriched HAP-GEL constructs with OD-MAPCs, compared to the undifferentiated MAPCloaded constructs, cell-free HAP-GEL with and without titanium, and PLGA scaffolds. The tissue-engineered TiO 2 -enriched HAP-GEL constructs with OD-MAPC aggregates present a potential useful therapeutic approach for calvaria bone regeneration.
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