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Roy V Sillitoe

Publications and source records attributed to Roy V Sillitoe.

12 recordsLinked to original sources
PubMed2007

SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA.

Myoclonus-dystonia syndrome (MDS) is a genetically heterogeneous disorder characterized by myoclonic jerks often seen in combination with dystonia and psychiatric co-morbidities and epilepsy. Mutations in the gene encoding epsilon-sarcoglycan (SGCE) have been found in some patients with MDS. SGCE is a maternally imprinted gene with the disease being inherited in an autosomal dominant pattern with reduced penetrance upon maternal transmission. In the central nervous system, epsilon-sarcoglycan is widely expressed in neurons of the cerebral cortex, basal ganglia, hippocampus, cerebellum and the olfactory bulb. epsilon-Sarcoglycan is located at the plasma membrane in neurons, muscle and transfected cells. To determine the effect of MDS-associated mutations on the function of epsilon-sarcoglycan we examined the biosynthesis and trafficking of wild-type and mutant proteins in cultured cells. In contrast to the wild-type protein, disease-associated epsilon-sarcoglycan missense mutations (H36P, H36R and L172R) produce proteins that are undetectable at the cell surface and are retained intracellularly. These mutant proteins become polyubiquitinated and are rapidly degraded by the proteasome. Furthermore, torsinA, that is mutated in DYT1 dystonia, a rare type of primary dystonia, binds to and promotes the degradation of epsilon-sarcoglycan mutants when both proteins are co-expressed. These data demonstrate that some MDS-associated mutations in SGCE impair trafficking of the mutant protein to the plasma membrane and suggest a role for torsinA and the ubiquitin proteasome system in the recognition and processing of misfolded epsilon-sarcoglycan.

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PubMed2004

Schizophrenia genetics: dysbindin under the microscope.

It is well established that genetic factors strongly contribute to the susceptibility of an individual to schizophrenia. Straub, Kendler and colleagues have published the first of several articles demonstrating a genetic association between schizophrenia and the gene encoding the dystrobrevin-binding protein dysbindin. Although no mutations in the dysbindin gene have been found, the recent identification of a specific risk haplotype in independent samples provides further evidence that dysbindin is a possible schizophrenia susceptibility gene.

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PubMed2004

Abnormal HNK-1 expression in the cerebellum of an N-CAM null mouse.

Human natural killer antigen-1 (HNK-1) is a carbohydrate epitope associated with sulfoglucuronylglycolipids and glycoproteins. Biochemical analyses have demonstrated associations between the HNK-1 epitope and isoforms of the neural cell adhesion molecule (N-CAM) family. In the cerebellum, HNK-1 is prominently expressed in Purkinje cell dendrites and Golgi cells. Purkinje cell expression of HNK-1 reveals an array of parasagittal stripes and transverse zones. Interestingly, the parasagittal expression pattern of HNK-1 is different from those reported with several other markers such as zebrin II/aldolase C and the small heat shock protein HSP25. N-CAM null knockout mice were used to explore the possible role of the HNK-1/N-CAM interaction during the topographical organization of the cerebellar cortex. N-CAM null mice have no N-CAM immunoreactivity but otherwise the cerebellum appears morphologically normal. Further, in the N-CAM null HNK-1 immunoreactivity is abolished from Purkinje cell dendrites but is retained on Golgi cells and neurons of the cerebellar nuclei. Despite the absence of N-CAM/HNK-1, parasagittal stripes and transverse zones in the cerebellum as revealed by using zebrin II immunocytochemistry appear normal.

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PubMed2004

Antigenic compartmentation of the primate and tree shrew cerebellum: a common topography of zebrin II in Macaca mulatta and Tupaia belangeri.

Despite the apparent uniformity in cellular composition of the adult cerebellar cortex, functional, anatomical, mutational and molecular maps all reveal a complex topography underlying the relatively simple architecture. In particular, zebrin II, a polypeptide antigen identified as aldolase C, is restricted to a subset of Purkinje cells that form a symmetrical and reproducible array of zones and stripes. The vermis of the well-studied rodent cerebellar cortex is divided into four transverse zones--anterior ( approximately lobules I-V), central ( approximately lobules VI and VII), posterior ( approximately lobule VIII) and nodular ( approximately lobules IX and X). Each transverse zone is further subdivided mediolaterally into parasagittal stripes. To gain insight into the evolution of cerebellar compartmentation, the pattern of zebrin II expression has been compared between the primate Macaca mulatta and the tree shrew Tupaia belangeri, and the results related to previous findings from other species. Although the somata of most Purkinje cells in the Macaca cerebellum express zebrin II, parasagittal stripes can still be delineated owing to the alternating high and low zebrin II immunoreactivity in the dendrites. In the macaque vermis, a complex set of zebrin II parasagittal compartments is found in all transverse zones. Unlike in rodents, in which uniform expression domains interrupt heterogeneous zones, zebrin II parasagittal stripes in the macaque cerebellum are seen throughout the vermis. In Tupaia, the parasagittal pattern of zebrin II expression also reveals a striking array of stripes in all lobules. The data suggest that cerebellar compartmentation in Tupaia belangeri more closely resembles that of primates than it does rodents or lagomorphs.

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PubMed2003

Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy.

The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.

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PubMed2003

Antigenic compartmentation of the cat cerebellar cortex.

Despite the apparent uniformity in cellular composition of the mammalian cerebellar cortex, a complex topography is revealed by several expression patterns. Zebrin II, a polypeptide antigen identified as aldolase C, is one such marker which, in several species of mammals, is restricted to a subset of Purkinje cells that are clustered together to form a symmetrical and reproducible array of zones and stripes. In rodents the cerebellar cortex is divided into four transverse zones--anterior, central, posterior, and nodular. Each transverse zone is further subdivided mediolaterally into an array of parasagittal stripes. The similar zone and stripe organization partitions the hemispheres. Based upon a novel whole mount immunohistochemical staining procedure, we have now identified homologous zones and stripes in the feline cerebellum. In the cat cerebellum the somata of most Purkinje cells express zebrin II but parasagittal stripes may still be delineated owing to the alternating high and low zebrin II expression levels in the dendritic arbors. As in rodents, the cat cerebellum consists of four transverse zones with each zone subdivided into a unique combination of zebrin II parasagittal stripes, suggesting that a common architecture underlies the organization of the mammalian cerebellum.

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PubMed2003

Topographical anatomy of the cerebellum in the guinea pig, Cavia porcellus.

Zebrin II/aldolase C is expressed in a stereotyped array of parasagittal bands and transverse zones in the cerebellum of many animals including birds and mammals. Here, section and whole mount immunohistochemistry has been used to characterize the expression of zebrin II in the cerebellum of the adult guinea pig. Purkinje cells in the adult guinea pig express zebrin II immunoreactivity at three different levels of intensity-high, medium and low. This expression pattern reveals an arrangement of parasagittal bands that are symmetrical about the midline and reproducible between individuals. The expression of zebrin II divides the vermis into four transverse expression domains from rostral to caudal: an anterior zone consisting of one zebrin II-immunoreactive band at the midline and at least three symmetrical bands laterally; a central zone, in which broad zebrin II-positive bands are separated by narrow bands of zebrin II-negative Purkinje cells that disappear caudally to leave no overt compartmentation; a posterior zone consisting of alternating bands of zebrin II-positive and -negative Purkinje cells; and finally, a nodular zone in which nearly all Purkinje cells express zebrin II. In the anterior and posterior hemispheres, zebrin II is also expressed in a banded pattern. These rostrocaudal and mediolateral patterns of zebrin II expression are reminiscent of those in other mammals including rabbit, rat, and mouse, and suggest that there may be a fundamental compartmental organization of the cerebellum that is conserved in mammals.

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PubMed2003

Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease.

Niemann Pick disease type C1 (NPC1) is an inherited, autosomal recessive, lipid-storage disorder with major neurological involvement. Purkinje cell death is a prominent feature of the neuropathology of NPC. We have investigated Purkinje cell death in two murine models of NPC1, BALB/c npc(nih) and C57BLKS/J spm. In both cases, extensive Purkinje cell death was found in the cerebellum. The pattern of Purkinje cell death is complex. First, zebrin II-negative Purkinje cells disappear, to leave survivors aligned in stripes that closely resemble the pattern revealed by using zebrin II immunocytochemistry. Subsequently, as the disease progresses, additional Purkinje cells die. At the terminal stages of the disease, the surviving Purkinje cells are concentrated in lobules IX and X of the posterior lobe vermis. Purkinje cell degeneration is accompanied by the ectopic expression of tyrosine hydroxylase and the small heat shock protein HSP25, both associated preferentially with the surviving cells. The pattern of cell death thus reflects the fundamental compartmentation of the cerebellum into zones and stripes.

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PubMed2003

Zebrin II compartmentation of the cerebellum in a basal insectivore, the Madagascan hedgehog tenrec Echinops telfairi.

The mammalian cerebellum is histologically uniform. However, underlying the simple laminar architecture is a complex arrangement of parasagittal stripes and transverse zones that can be revealed by the expression of zebrin II/aldolase C. The cerebellar cortex of rodents, for example, is organized into four transverse zones: anterior, central, posterior and nodular. Within the anterior and posterior zones, parasagittal stripes of Purkinje cells expressing zebrin II alternate with those that do not. Zonal boundaries appear to be independent of cerebellar lobulation. To explore this model further, and to broaden our understanding of the evolution of cerebellar patterning, zebrin II expression has been studied in the cerebellum of the Madagascan hedgehog tenrec (Echinops telfairi), a basal insectivore with a lissiform cerebellum with only five lobules. Zebrin II expression in the tenrec reveals an array of four transverse zones as in rodents, two with homogeneous zebrin II expression, two further subdivided into stripes, that closely resembles the expression pattern described in other mammals. We conclude that a zone-and-stripe organization may be a common feature of the mammalian cerebellar vermis and hemispheres, and that zonal boundaries and cerebellar lobules and fissures form independently.

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PubMed2002

Compartmentation of the rabbit cerebellar cortex.

The cytoarchitecture of the adult rabbit cerebellum is revealed by using zebrin II/aldolase c immunocytochemistry in both wholemount and sectioned material. Zebrin II is expressed by approximately half of the Purkinje cells of the cerebellar cortex. In most regions these form a symmetrical array of zebrin II positive and negative parasagittal bands. Four transverse expression domains are identified in the vermis: (1) an anterior zone, comprising four narrow bands, one at the midline and three laterally to either side, extending throughout the anterior lobe to the primary fissure; (2) a central zone with broad immunoreactive bands separated by narrow zebrin II negative bands that disappear caudally to leave no apparent compartmentation; (3) a posterior zone with prominent alternating zebrin II positive and negative bands; and (4) a nodular zone in which all Purkinje cells express zebrin II. In the hemispheres a striped topography is found in lobules HVI, HVII, and crus I, and all Purkinje cells are zebrin II+ in the flocculus and paraflocculus. Because of its importance for the classical conditioning of the eyeblink response, we made a detailed analysis of lobule HVI of the hemisphere. The immunocytochemical data show a complex substructure within HVI with three prominent zebrin II positive bands (probably homologous with P4a+, P4b+, and P5+ of rodents) separated by two zebrin II negative regions (P4- and P4b-). Thus, the organization of the rabbit cerebellum is consistent with the patterns described previously for rat, mouse, and opossum and suggests that there may be a common ground plan for the mammalian cerebellum.

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PubMed2002

Whole-mount immunohistochemistry: a high-throughput screen for patterning defects in the mouse cerebellum.

Large-scale mouse mutagenesis experiments now under way require appropriate screening methods. An important class of potential mutants comprises those with defects in the development of normal cerebellar patterning. Cerebellar defects are likely to be identified often because they typically result in ataxia. Immunohistochemistry (IHC) is commonly used to reveal cerebellar organization. In particular, the antigen zebrin II (=aldolase C), expressed by stripes of Purkinje cells, has been valuable in revealing cerebellar pattern abnormalities. The development of whole-mount procedures in Drosophila, chick, and Xenopus embryos allows complex patterns to be studied in situ while preserving the integrity of the structure. By combining procedures originally designed for embryonic and early postnatal tissue analyses, we have developed a whole-mount IHC protocol using anti-zebrin II, which reveals the complex topography of Purkinje cells in the adult mouse cerebellum. Furthermore, the procedure is effective with a number of other antigens and works well on both perfusion-fixed and immersion-fixed tissue. By use of this approach, normal adult murine cerebellar topography and patterning defects caused by mutation can be studied without the need for three-dimensional reconstruction.

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