Mapping of Purkinje Neuron Loss and Polyglucosan Body Accumulation in Hereditary Cerebellar Degeneration in Scottish Terriers

Abstract

A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid-Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P ¼ .0104). The degeneration was significantly more pronounced dorsally than ventrally (P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half (P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs (P ¼ .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non-membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.

Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed

“…These changes fit well with previous reports of CCD or cerebellar abiotrophy, where primary Purkinje neuron loss and secondary granular cell degeneration are most commonly reported [7, 11, 13, 14, 16]. Similar to previous studies, the HVs also demonstrated a characteristic distribution of cerebellar folial atrophy, with the dorsal and rostral vermis predominantly affected whilst the caudoventral regions appeared spared [10, 12, 14, 17]. Purkinje neuron loss and associated gliosis were more severe in Case 1.…”

“…CCD typically causes slowly progressive clinical signs related to diffuse cerebellar dysfunction, including a dysmetric and hypermetric cerebellar ataxia, intention tremors, menace response deficits and signs of central vestibular dysfunction, including nystagmus and loss of balance [12, 16]. Age of onset of clinical signs and the rate of progression vary between breeds, ranging from neonatal, as reported in Beagles and Rhodesian Ridgebacks [3, 13], and early onset from weeks to months of age in the majority of breeds [2, 6, 8, 9, 14, 16], up to adult-onset at months to years of age with a slower progression, seen in Old English Sheepdogs, Gordon Setters and Scottish Terriers [12, 15, 17]. …”

Canine Hereditary Ataxia

“…For example, increased numbers of polyglucosan bodies are found in the molecular layer in the Scottish Terrier. 28 Morphometric study of the cerebellum in Scottish Terriers revealed that the ventral part of the cerebellum is less severely affected 28 and this feature has also been reported in several breeds, such as Finnish Hounds, Beagles, 21 Old English Sheepdogs, and Gordon…”

Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24

“…Purebred dogs suffer from comparable neurodegenerative diseases affecting the cerebellar cortex referred to as cerebellar cortical degeneration, cerebellar abiotrophy or canine cerebellar or hereditary ataxia. Currently, hereditary cerebellar degenerative disorders have been described in over 20 breeds of dog [10], [11] with many more sporadic cases reported. In most dog breeds, the disorder causes slowly progressive degeneration of the cerebellar cortex, with dramatic Purkinje neuron loss resulting in a progressive gait dysfunction [10], [11].…”

“…Currently, hereditary cerebellar degenerative disorders have been described in over 20 breeds of dog [10], [11] with many more sporadic cases reported. In most dog breeds, the disorder causes slowly progressive degeneration of the cerebellar cortex, with dramatic Purkinje neuron loss resulting in a progressive gait dysfunction [10], [11]. Forms that primarily target the granular layer or produce ataxia without cell loss are also reported [12]–[18].…”