Purkinje Cell Apoptosis in Arabian Horses with Cerebellar Abiotrophy

Blanco, Ana María; Moyano, Rosario; Vivo, J.; Flores-Acuña, Rafaela; Molina, A.; Blanco, Carlos E.; Monterde, J. G.

doi:10.1111/j.1439-0442.2006.00836.x

Cited by 34 publications

(30 citation statements)

References 4 publications

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“…In horses, CA results in varying levels of ataxia with exaggerated forelimb movement, difficulty rising from a recumbent position, head tremors and lack of menace response (5). These signs are consistent with the histological hallmark of apoptosis of Purkinje neurons and subsequent disorganization of the three-layer cerebellar cortex structure (6). The loss of Purkinje neurons in CA has also been coupled with incomplete loss of granular neurons and a proliferation of Bergmann glia (7).…”

Section: Introductionsupporting

confidence: 83%

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

et al. 2016

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Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease that affects the Purkinje neurons of the cerebellum and causes ataxia in Arabian foals. Signs of CA are typically first recognized either at birth to any time up to 6 months of age. CA is inherited as an autosomal recessive trait and is associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (13074277G>A), located in the fourth exon of TOE1 and in proximity to MUTYH on the antisense strand. We hypothesize that unraveling the functional consequences of the CA SNP using RNA-seq will elucidate the molecular pathways underlying the CA phenotype. RNA-seq (100 bp PE strand-specific) was performed in cerebellar tissue from four CA-affected and five age-matched unaffected horses. Three pipelines for differential gene expression (DE) analysis were used (Tophat2/Cuffdiff2, Kallisto/EdgeR and Kallisto/Sleuth) with 151 significant DE genes identified by all three pipelines in CA-affected horses. TOE1 (Log2(foldchange)=0.92, p=0.66) and MUTYH (Log2(foldchange)=1.13, p=0.66) were not differentially expressed. Among the major pathways that were differentially expressed, genes associated with calcium homeostasis and specifically expressed in Purkinje neurons, CALB1 (Log2(foldchange)= −1.7, p<0.01) and CA8 (Log2(foldchange)= −0.97, p<0.01), were significantly down-regulated, confirming loss of Purkinje neurons. There was also a significant up-regulation of markers for microglial phagocytosis, TYROBP (Log2(foldchange)= 1.99, p<0.01) and TREM2 (Log2(foldchange)= 2.02, p<0.01). These findings reaffirm a loss of Purkinje neurons in CA-affected horses along with a potential secondary loss of granular neurons and activation of microglial cells.

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Section: Introductionsupporting

confidence: 83%

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

et al. 2016

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“…6 Lesions are much more severe, including marked degeneration, apoptosis, and loss of Purkinje cells. 2 In shivers horses, the focal nature of the lesion within the cerebellar nuclei, relatively normal numbers of Purkinje cells, and normal granular layer is entirely consistent with the absence of prominent signs of cerebellar ataxia. Purkinje cell numbers were only subjectively evaluated in a semiquantitative fashion in the present study, and it is possible that shivers horses had a regional loss of Purkinje cells.…”

Section: Discussionmentioning

confidence: 96%

The Equine Movement Disorder “Shivers” Is Associated With Selective Cerebellar Purkinje Cell Axonal Degeneration

et al. 2015

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''Shivers'' is a progressive equine movement disorder of unknown etiology. Clinically, horses with shivers show difficulty walking backward, assume hyperflexed limb postures, and have hind limb tremors during backward movement that resembles shivering. At least initially, forward movements are normal. Given that neither the neurophysiologic nor the pathologic mechanisms of the disease is known, nor has a neuroanatomic locus been identified, we undertook a detailed neuroanatomic and neuropathologic analysis of the complete sensorimotor system in horses with shivers and clinically normal control horses. No abnormalities were identified in the examined hind limb and forelimb skeletal muscles nor the associated peripheral nerves. Eosinophilic segmented axonal spheroids were a common lesion. Calretinin-positive axonal spheroids were present in many regions of the central nervous system, particularly the nucleus cuneatus lateralis; however, their numbers did not differ significantly from those of control horses. When compared to controls, calretinin-negative, calbindin-positive, and glutamic acid decarboxylase-positive spheroids were increased 80-fold in Purkinje cell axons within the deep cerebellar nuclei of horses with shivers. Unusual lamellar or membranous structures resembling marked myelin decompaction were present between myelin sheaths of presumed Purkinje cell axons in the deep cerebellar nuclei of shivers but not control horses. The immunohistochemical and ultrastructural characteristics of the lesions combined with their functional neuroanatomic distribution indicate, for the first time, that shivers is characterized by end-terminal neuroaxonal degeneration in the deep cerebellar nuclei, which results in context-specific hypermetria and myoclonus.

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“…Histopathologically, the cerebellum is characterised by apoptosis of the Purkinje cell layer. A pattern of inheritance consistent with an autosomal recessive trait has been observed, but a causative mutation has not yet been identified (Blanco et al 2006). …”

Section: Simple Genetic Diseases Of the Domestic Horsementioning

confidence: 99%

Equine clinical genomics: A clinician's primer

Brosnahan

Brooks

Antczak³

2010

Equine Veterinary Journal

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Summary The objective of this review is to introduce equine clinicians to the rapidly evolving field of clinical genomics with a vision of improving the health and welfare of the domestic horse. For fifteen years a consortium of veterinary geneticists and clinicians has worked together under the umbrella of The Horse Genome Project. This group, encompassing 22 laboratories in 12 countries, has made rapid progress, developing several iterations of linkage, physical and comparative gene maps of the horse with increasing levels of detail. In early 2006, the research was greatly facilitated when the U.S. National Human Genome Research Institute of the National Institutes of Health added the horse to the list of mammalian species scheduled for whole genome sequencing. The genome of the domestic horse has now been sequenced and is available to researchers worldwide in publicly accessible databases. This achievement creates the potential for transformative change within the horse industry, particularly in the fields of internal medicine, sports medicine and reproduction. The genome sequence has enabled the development of new genome-wide tools and resources for studying inherited diseases of the horse. To date, researchers have identified eleven mutations causing ten clinical syndromes in the horse. Testing is commercially available for all but one of these diseases. Future research will probably identify the genetic bases for other equine diseases, produce new diagnostic tests and generate novel therapeutics for some of these conditions. This will enable equine clinicians to play a critical role in ensuring the thoughtful and appropriate application of this knowledge as they assist clients with breeding and clinical decision-making.

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Purkinje Cell Apoptosis in Arabian Horses with Cerebellar Abiotrophy

Cited by 34 publications

References 4 publications

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

The Equine Movement Disorder “Shivers” Is Associated With Selective Cerebellar Purkinje Cell Axonal Degeneration

Equine clinical genomics: A clinician's primer

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