المؤلفون: Sara Lopes, Thorsten Schmidt, Clévio Nóbrega, Miguel Monteiro Lopes, Dineke S. Verbeek, Diana Lobo, Dina Pereira, Ana Vasconcelos-Ferreira, Luís Pereira de Almeida, Inês Morgado Martins, Rosário Faro

المساهمون: Movement Disorder (MD), Molecular Neuroscience and Ageing Research (MOLAR)

المصدر: Molecular Therapy, 30(1), 370-387. CELL PRESS
Mol Ther

مصطلحات موضوعية: congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Intranuclear Inclusions, Neuropathology, Mutant Huntingt, Biology, Neuroprotection, Mice, Cerebellar-Aaxiagene-Productcell-Lines, Drug Discovery, Genetics, medicine, Transcriptional regulation, Nuclear-Localization, Autophagy, Animals, Ataxin-3, Molecular Biology, Pharmacology, ULK2, Machado-Joseph Disease, ULK1, Dependovirus, medicine.disease, Cell biology, Disease Models, Animal, Molecular Medicine, Original Article, Polyglutamine-Expanded Ataxin-3, Rat Modelin-Vitro, medicine.symptom, Machado–Joseph disease

الوصف: Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in phagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ders. national funds through FCT (Foundation for Science and Technology) -Brain Health2020 projects CENTRO-01-0145-FEDER-000008, UID/NEU/04539/2020, CENTRO-01-0145-FEDER-022095, PTDC/NEU-NMC/0084/2014|POCI-01-0145-FEDER-016719, POCI-01-0145-FEDER-029716, POCI-01-0145-FEDER-016807, POCI-01-0145-FEDER-016390, POCI-01-0145-FEDER-032309, info:eu-repo/semantics/publishedVersion

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6624ead970bd32025df3f2fed67eab6Test
https://hdl.handle.net/11370/6e7d478b-8917-4de9-ba98-76e5ef115fc2Test

المؤلفون: Matos, C, Nóbrega, C, Louros, S, Almeida, B, Ferreiro, E, Valero, J, Almeida, L, Macedo-Ribeiro, S, Carvalho, A

المساهمون: Instituto de Investigação e Inovação em Saúde

مصطلحات موضوعية: Machado-joseph-disease, Protein ataxin-3, Polyglutamine disease, Mutant ataxin-3, Rat model, Huntingtin phosphorylation, Clinical-features, Expanded ataxin-3, Repeat expansion, Transgenic mice

الوصف: Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3–encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity.

وصف الملف: application/pdf; text/plain

العلاقة: info:eu-repo/grantAgreement/FCT/SFRH/SFRH/BD/47160/2008/PT; info:eu-repo/grantAgreement/FCT/SFRH/SFRH/BPD/70783/2010/PT; Journal of Cell Biology, vol. 212 (4), p. 465-480; http://jcb.rupress.org/content/212/4/465Test; http://hdl.handle.net/10216/108249Test

الإتاحة: https://doi.org/10.1083/jcb.201506025Test
http://hdl.handle.net/10216/108249Test

المؤلفون: An-Hsun Chou, Si-Ying Chen, Tu-Hsueh Yeh, Yi-Hsin Weng, Hung-Li Wang

المصدر: Neurobiology of Disease, Vol 41, Iss 2, Pp 481-488 (2011)

مصطلحات موضوعية: Spinocerebellar ataxia type 3, Ataxin-3, Polyglutamine-expanded ataxin-3, SCA3 transgenic mice, Cerebellum, Histone deacetylase, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. Previously, we prepared a SCA3 animal model by generating transgenic mice expressing disease-causing ataxin-3-Q79. Mutant ataxin-3-Q79 caused cerebellar malfunction of SCA3 transgenic mice by downregulating cerebellar mRNA expressions of proteins involved in synaptic transmission, signal transduction or regulating neuronal survival/differentiation. Histone acetylation, which is controlled by histone acetyltransferase and histone deacetylase (HDAC), plays an important role in regulating transcriptional activity. In the present study, we tested the hypothesis that ataxin-3-Q79 causes cerebellar transcriptional downregulation by inducing histone hypoacetylation and that HDAC inhibitor sodium butyrate (SB) alleviates ataxic symptoms of SCA3 transgenic mice by reversing ataxin-3-Q79-induced histone hypoacetylation and transcriptional repression. Compared to wild-type mice, H3 and H4 histones were hypoacetylated in the cerebellum of 6- to 8-month-old ataxin-3-Q79 transgenic mice, which displayed transcriptional downregulation and ataxic symptoms. Daily intraperitoneal administration of SB significantly reversed ataxin-3-Q79-induced histone hypoacetylation and transcriptional downregulation in the cerebellum of SCA3 transgenic mice. SB treatment also delayed the onset of ataxic symptoms, ameliorated neurological phenotypes and improved the survival rate of ataxin-3-Q79 transgenic mice. The present study provides the evidence that mutant ataxin-3-Q79 causes cerebellar transcriptional repression and ataxic symptoms of SCA3 transgenic mice by inducing hypoacetylation of histones H3 and H4. Our results suggest that sodium butyrate might be a promising therapeutic agent for SCA3.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996110003530Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/486188079be0447ab4e76c70641d3bd1Test

المؤلفون: An-Hsun Chou, Tu-Hsueh Yeh, Pin Ouyang, Ying-Ling Chen, Si-Ying Chen, Hung-Li Wang

المصدر: Neurobiology of Disease, Vol 31, Iss 1, Pp 89-101 (2008)

مصطلحات موضوعية: Spinocerebellar ataxia type 3, Ataxin-3, Polyglutamine-expanded ataxin-3, SCA3 transgenic mice, Cerebellum, Microarray analysis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: In the present study, we prepared a SCA3 animal model by generating transgenic mice expressing polyglutamine-expanded ataxin-3-Q79. Ataxin-3-Q79 was expressed in brain areas implicated in SCA3 neurodegeneration, including cerebellum, pontine nucleus and substantia nigra. Ataxin-3-Q79 transgenic mice displayed motor dysfunction with an onset age of 5–6 months, and neurological symptoms deteriorated in the following months. A prominent neuronal loss was not found in the cerebellum of 10 to 11-month-old ataxin-3-Q79 mice displaying pronounced ataxic symptoms, suggesting that instead of neuronal demise, ataxin-3-Q79 causes neuronal dysfunction of the cerebellum and resulting ataxia. To test the involvement of transcriptional dysregulation in ataxin-3-Q79-induced cerebellar malfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of ataxin-3-Q79 mice. Compared to non-transgenic mice or mice expressing wild-type ataxin-3-Q22, 10 to 11-month-old ataxin-3-Q79 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic neurotransmission, intracellular calcium signaling/mobilization or MAP kinase pathways, GABAA/B receptor subunits, heat shock proteins and transcription factor regulating neuronal survival and differentiation. Upregulated expressions of Bax, cyclin D1 and CDK5-p39, which may mediate neuronal death, were also observed in ataxin-3-Q79 transgenic mice. The involvement of transcriptional abnormality in initiating the pathological process of SCA3 was indicated by the finding that 4 to 5-month-old ataxin-3-Q79 mice, which did not display neurological phenotype, exhibited downregulated mRNA levels of genes involved in glutamatergic signaling and signal transduction. Our study suggests that polyglutamine-expanded ataxin-3 causes cerebellar dysfunction and ataxia by disrupting the normal pattern of gene transcriptions.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996108000673Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/147b561a68324264a53797da6300a29cTest

المؤلفون: An-Hsun Chou, Tu-Hsueh Yeh, Yu-Li Kuo, Yu-Cheng Kao, Mei-Jie Jou, Chia-Yu Hsu, Shu-Ru Tsai, Akira Kakizuka, Hung-Li Wang

المصدر: Neurobiology of Disease, Vol 21, Iss 2, Pp 333-345 (2006)

مصطلحات موضوعية: Spinocerebellar ataxia type 3, Ataxin-3, Polyglutamine-expanded ataxin-3, Apoptosis, Polyglutamine neurodegenerative disorders, Bax, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. In the present study, we expressed disease-causing mutant ataxin-3-Q79 in neuronal cultures of cerebellum, striatum and substantia nigra by using recombinant adenoviruses. Subsequently, SCA3 cellular model was used to investigate the molecular mechanism by which ataxin-3-Q79 causes neuronal death. TUNEL staining studies showed that ataxin-3-Q79 induced apoptotic death of cerebellar, striatal or substantia nigra neurons. Ataxin-3-Q79 activated caspase-3 and caspase-9 without inducing the formation of active caspase-8. Ataxin-3-Q79 promoted mitochondrial release of cytochrome c and Smac, which was preceded by the upregulation of Bax protein and downregulation of Bcl-xL protein expression. Real-time TaqMan RT-PCR assays demonstrated that ataxin-3-Q79 upregulated Bax mRNA level and downregulated Bcl-xL mRNA expression in striatal, cerebellar and substantia nigra neurons. Our results suggest that polyglutamine-expanded ataxin-3-Q79 activates mitochondrial apoptotic pathway and induces neuronal death by upregulating Bax expression and downregulating Bcl-xL expression.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996105002123Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/e776351009d2461f9297d9314b6e34e4Test

المؤلفون: Contessotto, Miriam Gisele Gasparotto, 1972, Garcia, Maria Cristina Cabral, Oliveira, Cristiano Luis Pinto de, 1975, Torriani, Iris Concepcion Linares de, 1934, Lopes-Cendes, Íscia Teresinha, 1964, Murai, Marcelo Jun, 1978

المساهمون: UNIVERSIDADE ESTADUAL DE CAMPINAS

المصدر: Repositório Institucional da Unicamp
Universidade Estadual de Campinas (UNICAMP)
instacron:UNICAMP
Repositório da Produção Científica e Intelectual da Unicamp

مصطلحات موضوعية: Doença de Machado-Joseph, Expanded ataxin-3, Machado-Joseph disease, Small-angle X-ray scattering, Artigo original, Ataxia, Raios X - Espalhamento a baixo ângulo

الوصف: Agradecimentos: The authors wish to thank Tatiany Marques for technical assistance, Drs. Celso Benedetti, Avram Slovic and Allen Liu for their support. We acknowledge the patients for donation of biological material. This study was supported by the São Paulo Research Foundation grants 01/07542-6, 2013/07559-3 (IL-C), 01/12346-1 (MGGC), 01/10658-6 (MCCG) and the Brazilian National Research Council-CNPq (ILT). Beam time granted at the SAXS Beamline of the Brazilian National Synchrotron Laboratory is gratefully acknowledged Abstract: An expansion of the polyglutamine (polyQ) tract within the deubiquitinase ataxin-3 protein is believed to play a role in a neurodegenerative disorder. Ataxin-3 contains a Josephin catalytic domain and a polyQ tract that renders it intrinsically prone to aggregate, and thus full-length protein is difficult to characterize structurally by high-resolution methods. We established a robust protocol for expression and purification of wild-type and expanded ataxin-3, presenting 19Q and 74Q, respectively. Both proteins are monodisperse as assessed by analytical size exclusion chromatography. Initial biophysical characterization was performed, with apparent transition melting temperature of expanded ataxin-3 lower than the wild-type counterpart. We further characterize the molecular envelope of wild-type and expanded polyQ tract in ataxin-3 using small angle X-ray scattering (SAXS). Characterization of protein-protein interactions between ataxin-3 and newly identified binding partners will benefit from our protocol CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Fechado

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::3888209f15dcce4c49e8bbf2e03113caTest

المؤلفون: Vasconcelos-Ferreira, Ana, Martins, Inês Morgado, Lobo, Diana, Pereira, Dina, Lopes, Miguel M., Faro, Rosário, Lopes, Sara M., Verbeek, Dineke, Schmidt, Thorsten, Nóbrega, Clévio, Pereira de Almeida, Luís

المساهمون: Sapientia

مصطلحات موضوعية: Polyglutamine-Expanded Ataxin-3, Mutant Huntingt, Intranuclear Inclusions, Nuclear-Localization, Cerebellar-Aaxiagene-Productcell-Lines, Rat Modelin-Vitro, Autophagy

الوصف: Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in phagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ders.

وصف الملف: application/pdf

الإتاحة: http://hdl.handle.net/10400.1/19229Test

المؤلفون: Sandra Macedo-Ribeiro, Luís Pereira de Almeida, Bruno Almeida, Clévio Nóbrega, Susana R. Louros, Ana Luísa Carvalho, Elisabete Ferreiro, Jorge Valero, Carlos A. Matos

المساهمون: Instituto de Investigação e Inovação em Saúde

المصدر: Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
The Journal of Cell Biology
Europe PubMed Central

مصطلحات موضوعية: Male, 0301 basic medicine, Time Factors, medicine.disease_cause, Synapse, Serine, 0302 clinical medicine, Transgenic mice, Phosphorylation, Ataxin-3, Mutant ataxin-3, Research Articles, Cerebral Cortex, Neurons, Mutation, Machado-Joseph Disease, Cell biology, Expanded ataxin-3, Biochemistry, Spinocerebellar ataxia, Rat model, RNA Interference, Protein ataxin-3, Machado–Joseph disease, Signal Transduction, congenital, hereditary, and neonatal diseases and abnormalities, Molecular Sequence Data, Gestational Age, Biology, Transfection, Neuroprotection, Article, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Rats, Wistar, Cell Biology, Repeat expansion, Fibroblasts, medicine.disease, Clinical-features, Repressor Proteins, Disease Models, Animal, Polyglutamine disease, HEK293 Cells, 030104 developmental biology, nervous system, Ataxin, Machado-joseph-disease, Nerve Degeneration, Synapses, Huntingtin phosphorylation, Peptides, 030217 neurology & neurosurgery

الوصف: Ataxin-3, the protein involved in spinocerebellar ataxia type 3 or Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded, and mutation of phosphorylation site S12 reduces aggregation, neuronal loss, and synapse loss.
Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3–encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity.

وصف الملف: application/pdf; text/plain

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::caa8599ef81658f39793e775da0d11fcTest
https://hdl.handle.net/10216/108249Test

المؤلفون: Yi Hsin Weng, Tu Hsueh Yeh, Hung Li Wang, Si Ying Chen, An Hsun Chou

المصدر: Neurobiology of Disease, Vol 41, Iss 2, Pp 481-488 (2011)

مصطلحات موضوعية: Transcriptional Activation, Genetically modified mouse, Cerebellum, congenital, hereditary, and neonatal diseases and abnormalities, Transgene, Down-Regulation, Mice, Transgenic, Nerve Tissue Proteins, Histone Deacetylases, lcsh:RC321-571, Mice, chemistry.chemical_compound, Downregulation and upregulation, Spinocerebellar ataxia type 3, medicine, Animals, Histone deacetylase, Enzyme Inhibitors, Polyglutamine-expanded ataxin-3, Ataxin-3, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Ataxin-1, biology, Nuclear Proteins, Acetylation, Sodium butyrate, Machado-Joseph Disease, Histone acetyltransferase, Molecular biology, Cell biology, Repressor Proteins, Phenotype, Histone, medicine.anatomical_structure, Ataxins, Neurology, chemistry, SCA3 transgenic mice, biology.protein, Butyric Acid

الوصف: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. Previously, we prepared a SCA3 animal model by generating transgenic mice expressing disease-causing ataxin-3-Q79. Mutant ataxin-3-Q79 caused cerebellar malfunction of SCA3 transgenic mice by downregulating cerebellar mRNA expressions of proteins involved in synaptic transmission, signal transduction or regulating neuronal survival/differentiation. Histone acetylation, which is controlled by histone acetyltransferase and histone deacetylase (HDAC), plays an important role in regulating transcriptional activity. In the present study, we tested the hypothesis that ataxin-3-Q79 causes cerebellar transcriptional downregulation by inducing histone hypoacetylation and that HDAC inhibitor sodium butyrate (SB) alleviates ataxic symptoms of SCA3 transgenic mice by reversing ataxin-3-Q79-induced histone hypoacetylation and transcriptional repression. Compared to wild-type mice, H3 and H4 histones were hypoacetylated in the cerebellum of 6- to 8-month-old ataxin-3-Q79 transgenic mice, which displayed transcriptional downregulation and ataxic symptoms. Daily intraperitoneal administration of SB significantly reversed ataxin-3-Q79-induced histone hypoacetylation and transcriptional downregulation in the cerebellum of SCA3 transgenic mice. SB treatment also delayed the onset of ataxic symptoms, ameliorated neurological phenotypes and improved the survival rate of ataxin-3-Q79 transgenic mice. The present study provides the evidence that mutant ataxin-3-Q79 causes cerebellar transcriptional repression and ataxic symptoms of SCA3 transgenic mice by inducing hypoacetylation of histones H3 and H4. Our results suggest that sodium butyrate might be a promising therapeutic agent for SCA3.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::764adb266c7489328157913970c7d266Test
http://www.sciencedirect.com/science/article/pii/S0969996110003530Test

المؤلفون: Tu Hsueh Yeh, Hung Li Wang, Pin Ouyang, Ying Ling Chen, Si Ying Chen, An Hsun Chou

المصدر: Neurobiology of Disease, Vol 31, Iss 1, Pp 89-101 (2008)

مصطلحات موضوعية: Genetically modified mouse, Cerebellum, Ataxia, Transcription, Genetic, Transgene, Blotting, Western, Gene Expression, Mice, Transgenic, Substantia nigra, Biology, lcsh:RC321-571, Mice, Spinocerebellar ataxia type 3, Heat shock protein, medicine, Animals, Humans, RNA, Messenger, Polyglutamine-expanded ataxin-3, Ataxin-3, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Neurodegeneration, Nuclear Proteins, Microarray analysis, Machado-Joseph Disease, medicine.disease, Immunohistochemistry, Molecular biology, Cell biology, Blotting, Southern, Disease Models, Animal, medicine.anatomical_structure, Neurology, nervous system, Ataxin, SCA3 transgenic mice, medicine.symptom, Peptides, Trinucleotide Repeat Expansion, Transcription Factors

الوصف: In the present study, we prepared a SCA3 animal model by generating transgenic mice expressing polyglutamine-expanded ataxin-3-Q79. Ataxin-3-Q79 was expressed in brain areas implicated in SCA3 neurodegeneration, including cerebellum, pontine nucleus and substantia nigra. Ataxin-3-Q79 transgenic mice displayed motor dysfunction with an onset age of 5-6 months, and neurological symptoms deteriorated in the following months. A prominent neuronal loss was not found in the cerebellum of 10 to 11-month-old ataxin-3-Q79 mice displaying pronounced ataxic symptoms, suggesting that instead of neuronal demise, ataxin-3-Q79 causes neuronal dysfunction of the cerebellum and resulting ataxia. To test the involvement of transcriptional dysregulation in ataxin-3-Q79-induced cerebellar malfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of ataxin-3-Q79 mice. Compared to non-transgenic mice or mice expressing wild-type ataxin-3-Q22, 10 to 11-month-old ataxin-3-Q79 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic neurotransmission, intracellular calcium signaling/mobilization or MAP kinase pathways, GABA(A/B) receptor subunits, heat shock proteins and transcription factor regulating neuronal survival and differentiation. Upregulated expressions of Bax, cyclin D1 and CDK5-p39, which may mediate neuronal death, were also observed in ataxin-3-Q79 transgenic mice. The involvement of transcriptional abnormality in initiating the pathological process of SCA3 was indicated by the finding that 4 to 5-month-old ataxin-3-Q79 mice, which did not display neurological phenotype, exhibited downregulated mRNA levels of genes involved in glutamatergic signaling and signal transduction. Our study suggests that polyglutamine-expanded ataxin-3 causes cerebellar dysfunction and ataxia by disrupting the normal pattern of gene transcriptions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e9fdf1f8f122593d4685fa8d75ff9efdTest
http://www.sciencedirect.com/science/article/pii/S0969996108000673Test