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‣ CCP1/Nna1 functions in protein turnover in mouse brain: Implications for cell death in Purkinje cell degeneration mice

BEREZNIUK, Iryna; SIRONI, Juan; CALLAWAY, Myrasol B.; CASTRO, Leandro M.; HIRATA, Izaura Y.; FERRO, Emer S.; FRICKER, Lloyd D.
Fonte: FEDERATION AMER SOC EXP BIOL Publicador: FEDERATION AMER SOC EXP BIOL
Tipo: Artigo de Revista Científica
Português
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Purkinje cell degeneration (pcd) mice have a mutation within the gene encoding cytosolic carboxypeptidase 1 (CCP1/Nna1), which has homology to metallocarboxypeptidases. To assess the function of CCP1/Nna1, quantitative proteomics and peptidomics approaches were used to compare proteins and peptides in mutant and wild-type mice. Hundreds of peptides derived from cytosolic and mitochondrial proteins are greatly elevated in pcd mouse hypothalamus, amygdala, cortex, prefrontal cortex, and striatum. However, the major proteins detected on 2-D gel electrophoresis were present in mutant and wild-type mouse cortex and hypothalamus at comparable levels, and proteasome activity is normal in these brain regions of pcd mice, suggesting that the increase in cellular peptide levels in the pcd mice is due to reduced degradation of the peptides downstream of the proteasome. Both nondegenerating and degenerating regions of pcd mouse brain, but not wild-type mouse brain, show elevated autophagy, which can be triggered by a decrease in amino acid levels. Taken together with previous studies on CCP1/Nna1, these data suggest that CCP1/Nna1 plays a role in protein turnover by cleaving proteasome-generated peptides into amino acids and that decreased peptide turnover in the pcd mice leads to cell death.-Berezniuk...

‣ Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel γ subunit

Chen, Lu; Bao, Shaowen; Qiao, Xiaoxi; Thompson, Richard F.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 12/10/1999 Português
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The waggler, a neurological mutant mouse with a disrupted putative neuronal Ca2+ channel γ subunit, exhibits a cerebellar granule cell-specific brain-derived neurotrophic factor deficit, severe ataxia, and impaired eyeblink conditioning. Here, we show that multiple synapses of waggler cerebellar granule cells are arrested at an immature stage during development. Synaptic transmission is reduced at parallel fiber–Purkinje cell synapses. The Golgi cell–granule cell synaptic currents show immature kinetics associated with reduced γ-aminobutyric acid type A receptor α6 subunit expression in granule cells. In addition, the mossy fiber–granule cell synapses exhibit N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs), but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs. Our results suggest that voltage-dependent Ca2+ channels are involved in synapse maturation. This deficient synaptic transmission in the waggler cerebellum may account for their behavioral deficits.

‣ Defective γ-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice

Slesinger, Paul A.; Stoffel, Markus; Jan, Yuh Nung; Jan, Lily Y.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 28/10/1997 Português
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Stimulation of inhibitory neurotransmitter receptors, such as γ-aminobutyric acid type B (GABAB) receptors, activates G protein-gated inwardly rectifying K+ channels (GIRK) which, in turn, influence membrane excitability. Seizure activity has been reported in a Girk2 null mutant mouse lacking GIRK2 channels but showing normal cerebellar development as well as in the weaver mouse, which has mutated GIRK2 channels and shows abnormal development. To understand how the function of GIRK2 channels differs in these two mutant mice, we compared the G protein-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from Girk2 null mutant and weaver mutant mice with those from wild-type mice. Activation of GABAB receptors in wild-type granule cells induced an inwardly rectifying K+ current, which was sensitive to pertussis toxin and inhibited by external Ba2+ ions. The amplitude of the GABAB receptor-activated current was severely attenuated in granule cells isolated from both weaver and Girk2 null mutant mice. By contrast, the G protein-gated inwardly rectifying current and possibly the agonist-independent basal current appeared to be less selective for K+ ions in weaver but not Girk2 null mutant granule cells. Our results support the hypothesis that a nonselective current leads to the weaver phenotype. The loss of GABAB receptor-activated GIRK current appears coincident with the absence of GIRK2 channel protein and the reduction of GIRK1 channel protein in the Girk2 null mutant mouse...

‣ Impaired Eye-Blink Conditioning in waggler, a Mutant Mouse With Cerebellar BDNF Deficiency

Bao, Shaowen; Chen, Lu; Qiao, Xiaoxi; Knusel, Beat; Thompson, Richard F.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /09/1998 Português
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In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.

‣ The wasted mutant mouse. II. Immunological abnormalities in a mouse described as a model of ataxia-telangiectasia.

Kaiserlian, D; Savino, W; Uriel, J; Hassid, J; Dardenne, M; Bach, J F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1986 Português
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Ataxia-telangiectasia (AT) is a complex multiparametric disease associating oculocutaneous telangiectasias, cerebellar ataxia, elevated chromosomal aberration frequency and varied degrees of immunodeficiency. Recently a wasted mutant mouse (wst) has been described as an animal model of AT. We have looked in the wasted mutants for the presence of immune and endocrine abnormalities characteristic of AT. In contrast to the T cell immunodeficiency in AT, wasted mutants had a marked hypoplasia of all lymphoid organs, which affected both T and B lymphocyte subsets. The marked thymic atrophy appearing at the final stage of their disease did not modify the endocrine function of the thymic epithelium which produced normal levels of the thymic hormone thymulin. Although in vitro interleukin 2 (IL-2) production by splenic T cells in response to Con A was markedly diminished, these mice presented normal T and B cell proliferative responses to mitogens. Finally, no significant increase in serum alpha-fetoprotein level (a typical marker of AT) was found throughout the course of the disease. Although by many aspects, i.e. neurological disorder, chromosomal aberrations and early death, wasted mice presented similarities with human AT, major discrepancies in the typical features of immune abnormalities were found between the mouse model and the human disease.

‣ Astrotactin: a novel neuronal cell surface antigen that mediates neuron- astroglial interactions in cerebellar microcultures

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/02/1988 Português
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A microculture system for mouse cerebellar cells has been used to identify an immune activity, raised in rabbits against postnatal cerebellar cells, that blocks neuron-glial interactions in vitro. In the presence of blocking antibodies, stable neuron-glial contacts did not form and neuronal induction of glial process outgrowth did not occur. Subsequently, neurons were randomly arranged in the cultures rather than organized along the arms of astroglia. We have named the immune activity that blocks neuron-astroglial interactions anti- astrotactin. Partial purification of the anti-astrotactin blocking antibodies was obtained by cellular absorption with PC12 cells, a clonal cell line which expresses both the N-CAM and NILE (Ng-CAM, L1) glycoproteins. Subsequent absorption with purified cerebellar granule cells, but not with astroglial cells, removed the blocking activity, suggesting that the antigen(s) bound by blocking antibodies are neuronal. Immunoprecipitation of [35S]methionine- or [3H]fucose- radiolabeled Triton extracts of early postnatal cerebellar cells showed that the unabsorbed antiserum recognized a large number of proteins. Among these were bands with apparent molecular masses of N-CAM (180 and 140 kD) and NILE (230 kD). After absorption of the immune serum with PC12 cells...

‣ Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering

Zhou, Yu Dong; Turner, Timothy J; Dunlap, Kathleen
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
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Tottering, a mouse model for absence epilepsy and cerebellar ataxia, carries a mutation in the gene encoding class A (P/Q-type) Ca2+ channels, the dominant exocytotic Ca2+ channel at most synapses in the mammalian central nervous system. Comparing tottering to wild-type mice, we have studied glutamatergic transmission between parallel fibres and Purkinje cells in cerebellar slices. Results from biochemical assays and electrical field recordings demonstrate that glutamate release from parallel fibre terminals of the tottering mouse is controlled largely by class B Ca2+ channels (N-type), in contrast to the P/Q-channels that dominate release from wild-type terminals. Since N-channels, in a variety of assays, are more effectively inhibited by G proteins than are P/Q-channels, we tested whether synaptic transmission between parallel fibres and Purkinje cells in tottering mice was more susceptible to inhibitory modulation by G protein-coupled receptors than in their wild-type counterparts. GABAB receptors and α2-adrenergic receptors (activated by bath application of transmitters) produced a three- to fivefold more potent inhibition of transmission in tottering than in wild-type synapses. This increased modulation is likely to be important for cerebellar transmission in vivo...

‣ Analysis of Transcriptional Profiles and Functional Clustering of Global Cerebellar Gene Expression in PCD3J Mice

Ford, Gregory D.; Ford, Byron D.; Steele, Ernest C.; Gates, Alicia; Hood, Darryl; Matthews, Mika A.B.; Mirza, Sophia; MacLeish, Peter R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The Purkinje cell degeneration (PCD) mutant mouse is characterized by a degeneration of cerebellar Purkinje cells and progressive ataxia. To identify the molecular mechanisms that lead to the death of Purkinje neurons in PCD mice, we used Affymetrix microarray technology to compare cerebellar gene expression profiles in pcd3J mutant mice 14 days of age (prior to Purkinje cell loss) to unaffected littermates. Microarray analysis, Ingenuity Pathway Analysis (IPA) and Expression Analysis Systematic Explorer (EASE) software were used to identify biological and molecular pathways implicated in the progression of Purkinje cell degeneration. IPA analysis indicated that mutant pcd3J mice showed dysregulation of specific processes that may lead to Purkinje cell death, including several molecules known to control neuronal apoptosis such as Bad, CDK5 and PTEN. These findings demonstrate the usefulness of these powerful microarray analysis tools and have important implications for understanding the mechanisms of selective neuronal death and for developing therapeutic strategies to treat neurodegenerative disorders.

‣ Sensorimotor enhancement in mouse mutants lacking the Purkinje cell-specific Gi/o modulator, Pcp2(L7)

Iscru, Emilia; Serinagaoglu, Yelda; Schilling, Karl; Tian, Jinbin; Bowers-Kidder, Stephanie L.; Zhang, Rui; Morgan, James I.; DeVries, A. Courtney; Nelson, Randy J.; Zhu, Michael X.; Oberdick, John
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Pcp2(L7) is a GoLoco domain protein specifically and abundantly expressed in cerebellar Purkinje cells. It has been hypothesized to “tune” Gi/o-coupled receptor modulation of physiological effectors, including the P-type Ca2+ channel. We have analyzed a mouse mutant in which the Pcp2(L7) gene was inactivated and find significant anatomical, behavioral and electrophysiological changes. Anatomically, we observed mild cerebellar hypoplasia. Behaviorally, the mutants were altered in modalities atypical for a traditional cerebellar mutant, and oddly, all of these changes could be considered functional enhancements. This includes increased asymptotic performance in gross motor learning, increased rate of acquisition in tone-conditioned fear, and enhanced pre-pulse inhibition of the acoustic startle response. Electrophysiological analysis of Purkinje cells in the mutants reveals depression of the complex spike waveform that may underlie the behavioral changes. Based on these observations we suggest that the Pcp2(L7) protein acts as a sensorimotor damper that modulates time- and sense-dependent changes in motor responses.

‣ Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the Expression of Eaat4

Sachs, Andrew J.; David, Samuel A.; Haider, Neena B.; Nystuen, Arne M.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 14/12/2009 Português
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The weeble mutant mouse has a frame shift mutation in inositol polyphosphate 4-phosphatase type I (Inpp4a). The phenotype is characterized by an early onset cerebellar ataxia and neurodegeneration, especially apparent in the Purkinje cells. Purkinje cell loss is a common pathological finding in many human and mouse ataxic disorders. Here we show that in the Inpp4awbl mutant, Purkinje cells are lost in a specific temporal and spatial pattern. Loss occurs early in postnatal development; however, prior to the appearance of climbing fibers in the developing molecular layer, the mutant has a normal complement of Purkinje cells and they are properly positioned. Degeneration and reactive gliosis are present at postnatal day 5 and progress rapidly in a defined pattern of patches; however, Inpp4a is expressed uniformly across Purkinje cells. In late stage mutants, patches of surviving Purkinje cells appear remarkably normal with the exception that the climbing fibers have been excessively eliminated. Surviving Purkinje cells express Eaat4, a glutamate transporter that is differentially expressed in subsets of Purkinje cells during development and into adult stages. Prior to Purkinje cell loss, reactive gliosis and dendritic atrophy can be seen in Eaat4 negative stripes. Our data suggest that Purkinje cell loss in the Inpp4awbl mutant is due to glutamate excitotoxicity initiated by the climbing fiber...

‣ Transplantation of Embryonic and Adult Neural Stem Cells in the Granuloprival Cerebellum of the Weaver Mutant Mouse

Chen, K. Amy; Lanuto, Derek; Zheng, Tong; Steindler, Dennis A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/2009 Português
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Numerous studies have explored the potential of different stem and progenitor cells to replace at-risk neuronal populations in a variety of neurodegenerative disease models. This study presents data from a side by side approach of engrafting two different stem/progenitor cell populations within the postnatal cerebellum of the weaver neurological mutant mouse: cerebellar-derived multipotent astrocytic stem cells (MASCs) and embryonic stem cell-derived neural precursor (ESNPs), for comparative analysis. We show here that both donor populations survive, migrate, and appear to initiate differentiation into neurons within the granuloprival host environment. Neither of these disparate stem/progenitor cell populations adopted significant region-specific identities despite earlier studies that suggested the potential of these cells to respond to in vivo cues when placed in a permissive/instructive milieu. However, data presented here suggest that molecular and cellular deficits present within weaver homozygous or heterozygous brains may promote a slightly more positive donor cell response towards acquisition of neuronal phenotype. Hence it is likely that a fine balance exists between a compromised host environment that is amenable to cell replacement and that of a degenerating cellular milieu where it is perhaps too deleterious to support extensive neuronal differentiation and functional cellular integration. These findings join a growing list of studies that show successful cell replacement depends largely on the interplay between the potentiality of the donor cells and the specific pathological conditions of the recipient environment...

‣ Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Aguilar, Andrea; Meunier, Alice; Strehl, Laetitia; Martinovic, Jelena; Bonniere, Maryse; Attie-Bitach, Tania; Encha-Razavi, Féréchté; Spassky, Nathalie
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results...

‣ Expression of Caytaxin Protein in Cayman Ataxia Mouse Models Correlates with Phenotype Severity

Sikora, Kristine M.; Nosavanh, LaGina M.; Kantheti, Prameela; Burmeister, Margit; Hortsch, Michael
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 30/11/2012 Português
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Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt) rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcayjit (jittery) and Atcayswd (sidewinder) mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcayji-hes (hesitant) line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin’s physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms...

‣ The cerebellum: a new key structure in the navigation system

Rochefort, Christelle; Lefort, Julie M.; Rondi-Reig, Laure
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 13/03/2013 Português
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Early investigations of cerebellar function focused on motor learning, in particular on eyeblink conditioning and adaptation of the vestibulo-ocular reflex, and led to the general view that cerebellar long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses is the neural correlate of cerebellar motor learning. Thereafter, while the full complexity of cerebellar plasticities was being unraveled, cerebellar involvement in more cognitive tasks—including spatial navigation—was further investigated. However, cerebellar implication in spatial navigation remains a matter of debate because motor deficits frequently associated with cerebellar damage often prevent the dissociation between its role in spatial cognition from its implication in motor function. Here, we review recent findings from behavioral and electrophysiological analyses of cerebellar mutant mouse models, which show that the cerebellum might participate in the construction of hippocampal spatial representation map (i.e., place cells) and thereby in goal-directed navigation. These recent advances in cerebellar research point toward a model in which computation from the cerebellum could be required for spatial representation and would involve the integration of multi-source self-motion information to: (1) transform the reference frame of vestibular signals and (2) distinguish between self- and externally-generated vestibular signals. We eventually present herein anatomical and functional connectivity data supporting a cerebello-hippocampal interaction. Whilst a direct cerebello-hippocampal projection has been suggested...

‣ Kv3.3 channels harbouring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells

Irie, Tomohiko; Matsuzaki, Yasunori; Sekino, Yuko; Hirai, Hirokazu
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
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Abstract The cerebellum plays crucial roles in controlling sensorimotor functions. The neural output from the cerebellar cortex is transmitted solely by Purkinje cells (PCs), whose impairment causes cerebellar ataxia. Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease, and SCA13 patients exhibit cerebellar atrophy and cerebellar symptoms. Recent studies have shown that missense mutations in the voltage-gated K+ channel Kv3.3 are responsible for SCA13. In the rodent brain, Kv3.3 mRNAs are expressed most strongly in PCs, suggesting that the mutations severely affect PCs in SCA13 patients. Nevertheless, how these mutations affect the function of Kv3.3 in PCs and, consequently, the morphology and neuronal excitability of PCs remains unclear. To address these questions, we used lentiviral vectors to express mutant mouse Kv3.3 (mKv3.3) channels harbouring an R424H missense mutation, which corresponds to the R423H mutation in the Kv3.3 channels of SCA13 patients, in mouse cerebellar cultures. The R424H mutant-expressing PCs showed decreased outward current density, broadened action potentials and elevated basal [Ca2+]i compared with PCs expressing wild-type mKv3.3 subunits or those expressing green fluorescent protein alone. Moreover...

‣ Purkinje Cell Compartmentation in the Cerebellum of the Lysosomal Acid Phosphatase 2 Mutant Mouse (Nax - Naked-Ataxia Mutant Mouse)

Bailey, Karen; Rahimi Balaei, Maryam; Mannan, Ashraf; Del Bigio, Marc R.; Marzban, Hassan
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 10/04/2014 Português
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The Acp2 gene encodes the beta subunit of lysosomal acid phosphatase, which is an isoenzyme that hydrolyzes orthophosphoric monoesters. In mice, a spontaneous mutation in Acp2 results in severe cerebellar defects. These include a reduced size, abnormal lobulation, and an apparent anterior cerebellar disorder with an absent or hypoplastic vermis. Based on differential gene expression in the cerebellum, the mouse cerebellar cortex can normally be compartmentalized anteroposteriorly into four transverse zones and mediolaterally into parasagittal stripes. In this study, immunohistochemistry was performed using various Purkinje cell compartmentation markers to examine their expression patterns in the Acp2 mutant. Despite the abnormal lobulation and anterior cerebellar defects, zebrin II and PLCβ4 showed similar expression patterns in the nax mutant and wild type cerebellum. However, fewer stripes were found in the anterior zone of the nax mutant, which could be due to a lack of Purkinje cells or altered expression of the stripe markers. HSP25 expression was uniform in the central zone of the nax mutant cerebellum at around postnatal day (P) 18–19, suggesting that HSP25 immunonegative Purkinje cells are absent or delayed in stripe pattern expression compared to the wild type. HSP25 expression became heterogeneous around P22–23...

‣ Purkinje cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher

Sillitoe, Roy V.; George-Jones, Nicholas A.; Millen, Kathleen J.; Hawkes, Richard
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The cerebellar morphological phenotype of the spontaneous neurological mutant mouse dreher (Lmx1adr-J) results from cell fate changes in dorsal midline patterning involving the roof plate and rhombic lip. Positional cloning revealed that the gene Lmx1a, which encodes a LIM homeodomain protein, is mutated in dreher, and is expressed in the developing roof plate and rhombic lip. Loss of Lmx1a causes reduction of the roof plate, an important embryonic signaling center, and abnormal cell fate specification within the embryonic cerebellar rhombic lip. In adult animals, these defects result in variable, medial fusion of the cerebellar vermis and posterior cerebellar vermis hypoplasia. It is unknown whether deleting Lmx1a results in displacement or loss of specific lobules in the vermis. To distinguish between an ectopic and an absent vermis, the expression patterns of two Purkinje cell specific compartmentation antigens, zebrin II/aldolase C and the small heat shock protein HSP25, were analyzed in dreher cerebella. The data reveal that despite the reduction in volume and abnormal foliation of the cerebellum, the transverse zones and parasagittal stripe arrays characteristic of the normal vermis are present in dreher, but may be highly distorted. In dreher mutants with a severe phenotype...

‣ GD3- and O-acetylated GD3-gangliosides in the GM2 synthase-deficient mouse brain and their immunohistochemical localization

Matsuda, Junko; Vanier, Marie T.; Popa, Iuliana; Portoukalian, Jacques; Suzuki, Kunihiko
Fonte: The Japan Academy Publicador: The Japan Academy
Tipo: Artigo de Revista Científica
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Gangliosides in the brain of the knockout mouse deficient in the activity of β1,4 N-acetylgalactosaminyl transferase (β1,4 GalNAc-T)(GM2 synthase) consisted of nearly exclusively of GM3- and GD3-gangliosides as expected from the known substrate specificity of the enzyme and in confirmation of the initial reports from two laboratories that generated the mutant mouse experimentally. The total molar amount of gangliosides was approximately 30% higher in the mutant mouse brain than that in the wild-type brain. However, contrary to the initial reports, one-fourth of total GD3-ganglioside was O-acetylated. It reacted positively with an anti-O-acetylated GD3 monoclonal antibody and disappeared with a corresponding increase in GD3-ganglioside after mild alkaline treatment. The absence of O-acetylated GD3 in the initial reports can be explained by the saponification step included in their analytical procedures. Although quantitatively much less and identification tentative, we also detected GT3 and O-acetylated GT3. Anti-GD3 and anti-O-acetylated GD3 monoclonal antibodies gave positive reactions in the brain of mutant mouse as expected from the analytical results. Either antibody barely stained wild-type brain except for immunoreactivity of GD3 in the cerebellar Purkinje cells. The distributions of GD3 and O-acetylated GD3 in the brain of mutant mouse were similar but differential localization was noted in the cerebellar Purkinje cells and cerebral cortex.

‣ Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas

Steadman, Patrick E.; Ellegood, Jacob; Szulc, Kamila U.; Turnbull, Daniel H.; Joyner, Alexandra L.; Henkelman, R. Mark; Lerch, Jason P.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals’ genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors...

‣ Genexpression von potentiellen Modulatoren inhibitorischer Neurotransmission in der Maus-Mutante Lurcher; Gene expression of potential modulators of inhibitory neurotransmission in the Lurcher mutant mouse

Schmeh, Isabella Maria
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Die Maus-Mutante Lurcher ist ein Tiermodell für die spinocerebelläre Ataxie und durch einen primären Untergang der Purkinjezellen charakterisiert. Im Gegensatz zur massiven sekundären Degeneration von Körnerzellen und Neuronen der inferioren Olive fällt der Verlust von Neuronen der tiefen Kleinhirnkerne verhältnismäßig gering aus. Diesen Kerngebieten wird eine gewisse kompensatorische Fähigkeit zugeschrieben. Während des Purkinezelluntergangs kann eine verstärkte inhibitorische synaptische Erregungsübertragung nachgewiesen werden. Immunhistochemisch findet sich in vier Wochen alten Lc eine Zunahme kleiner GABAerger Neurone und eine Größenzunahme der Endknöpfchen bei relativ schwach ausgeprägtem Verlust GABAerger Synapsen. Um die stattfindenden Vorgänge genauer zu beleuchten wurde in dieser Arbeit die Genexpression potentieller Modulatoren der inhibitorischen synaptischen Erregungsüberleitung untersucht. Mittels quantitativer real-time PCR konnte eine Herunterregulation der Genexpression des GABARAP und der gamma2-Untereinheit des GABA-A-Rezeptors bei 14 Tage alten Mäusen nachgewiesen werden. Die Herunterregulation beider Proteine kann zur Zunahme von ungeclusterten Rezeptoren mit höherer GABA-Affinität und schnellerer Wiederöffnungszeit beitragen. Dies könnte eine bessere Verwertung herabgesetzter GABA-Konzentrationen ermöglichen. Durch eine verringerte Anzahl von Bindungsstellen für gamma2 und eine relative Zunahme von Rezeptoren...