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1.
Cell ; 107(5): 555-7, 2001 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-11733054

RESUMO

Three papers published recently in Cell bring the power of human genetics, Drosophila genetics, and genomics to bear on the understanding of fragile X syndrome. They provide further support for the importance of local protein synthesis within a neuron as a determinant of proper synaptogenesis and the development of cognitive abilities.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Motivos de Aminoácidos , Animais , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteína do X Frágil da Deficiência Intelectual , Humanos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Ligação Proteica , RNA/química , RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Ribossomos/metabolismo , Sinapses/fisiologia
2.
Neurobiol Dis ; 8(6): 974-81, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11741393

RESUMO

The expansion of a polyglutamine tract in the ataxin-1 protein beyond a critical threshold causes spinocerebellar ataxia type 1 (SCA1). To investigate the mechanism of neuronal degeneration in SCA1, we analyzed the phenotype of an SCA1 transgenic mouse model in the absence of p53, an important regulator of cell death. p53 deficiency did not affect the early features of SCA1 mice such as impaired motor coordination and ataxin-1 nuclear inclusion formation but caused a notable reduction in later pathological features, including Purkinje cell heterotopia, dendritic thinning, and molecular layer shrinkage. To determine if this protective effect was mediated by an anti-apoptotic property of p53 deficiency, we looked for apoptosis in SCA1 mice but failed to detect any evidence of it even in the presence of p53. We propose that p53 acts after the initial pathogenic events in SCA1 to promote the progression of neuronal degeneration in SCA1 mice, but this activity may be unrelated to apoptosis.


Assuntos
Apoptose/genética , Deleção de Genes , Degeneração Neural/genética , Células de Purkinje/metabolismo , Ataxias Espinocerebelares/genética , Proteína Supressora de Tumor p53/deficiência , Animais , Ataxina-1 , Ataxinas , Feminino , Genótipo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Equilíbrio Postural/fisiologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia , Proteína Supressora de Tumor p53/genética
3.
Neuron ; 31(6): 875-6, 2001 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-11580886

RESUMO

The polyglutamine diseases include at least nine neurodegenerative disorders. Accumulation of mutant protein with a toxic gain-in function in the nucleus appears to be the pathological basis of these diseases. In this issue of Neuron, La Spada et al. (2001) provide insight into the cell specificity of pathology for a polyglutamine disease by relating SCA7-induced retinal degeneration to a disruption of the photoreceptor-specific transcription factor CRX.


Assuntos
Núcleo Celular/metabolismo , Repetições Minissatélites , Proteínas do Tecido Nervoso/fisiologia , Doenças Neurodegenerativas/genética , Proteínas Nucleares/fisiologia , Peptídeos/química , Fatores de Transcrição/fisiologia , Animais , Ataxina-7 , Modelos Animais de Doenças , Proteínas do Olho/química , Proteínas do Olho/genética , Proteínas do Olho/fisiologia , Proteínas de Homeodomínio/fisiologia , Humanos , Substâncias Macromoleculares , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Ligação Proteica , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Transativadores/fisiologia , Ativação Transcricional , Repetições de Trinucleotídeos
4.
Hum Mol Genet ; 10(20): 2307-11, 2001 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-11673415

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is a relatively rare autosomal-dominant neurological disorder. SCA1 has the intriguing feature that the disease-causing mutation is the expansion of an unstable trinucleotide repeat, specifically a CAG repeat that encodes the amino acid glutamine in ataxin-1. During the past 10 years, substantial progress has been made towards understanding the pathogenic mechanism in this disease. The nucleus has been identified as the subcellular site where the mutant protein acts to cause disease. Evidence indicates that expansion of the glutamine tract alters the folding properties of ataxin-1. Finally, several cellular pathways have been identified which are able to impinge on the SCA1 disease process. The characterization of these pathways and their role in SCA1 will guide research over the next several years.


Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Peptídeos/genética , Ataxias Espinocerebelares/genética , Animais , Ataxina-1 , Ataxinas , Modelos Animais de Doenças , Ordem dos Genes/genética , Humanos , Biologia Molecular , Repetições de Trinucleotídeos/genética
5.
Am J Pathol ; 159(3): 905-13, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11549583

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluRDelta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKCgamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKCgamma localization at the Purkinje cell dendritic membrane and decreased detection of PKCgamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKCgamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.


Assuntos
Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteínas Nucleares/fisiologia , Células de Purkinje/metabolismo , Animais , Ataxina-1 , Ataxinas , Cisteína Endopeptidases/metabolismo , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Dendritos/metabolismo , Membranas Intracelulares/metabolismo , Isoenzimas/metabolismo , Camundongos , Camundongos Transgênicos/genética , Complexos Multienzimáticos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Complexo de Endopeptidases do Proteassoma , Proteína Quinase C/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Distribuição Tecidual , Ubiquitinas/metabolismo
6.
Hum Mol Genet ; 10(14): 1511-8, 2001 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-11448943

RESUMO

Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits--all components of the cellular protein re-folding and degradation machinery--we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.


Assuntos
Proteínas de Choque Térmico HSP70/genética , Atividade Motora , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/prevenção & controle , Proteínas Nucleares/genética , Estrutura Terciária de Proteína/genética , Repetições de Trinucleotídeos/genética , Animais , Ataxina-1 , Ataxinas , Tronco Encefálico/patologia , Cerebelo/patologia , Expressão Gênica , Técnicas In Vitro , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Conformação Proteica , Células de Purkinje/patologia
8.
J Neurophysiol ; 85(4): 1750-60, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11287496

RESUMO

Cerebellar Purkinje cells (PCs) from spinocerebellar ataxia type 1 (SCA1) transgenic mice develop dendritic and somatic atrophy with age. Inositol 1,4,5-trisphosphate receptor type 1 and the sarco/endoplasmic reticulum Ca(2+) ATPase pump, which regulate [Ca(2+)](i), are expressed at lower levels in these cells compared with the levels in cells from wild-type (WT) mice. To examine PCs in SCA1 mice, we used whole-cell patch clamp recording combined with fluorometric [Ca(2+)](i) and [Na(+)](i) measurements in cerebellar slices. PCs in SCA1 mice had Na(+) spikes, Ca(2+) spikes, climbing fiber (CF) electrical responses, parallel fiber (PF) electrical responses, and metabotropic glutamate receptor (mGluR)-mediated, PF-evoked Ca(2+) release from intracellular stores that were qualitatively similar to those recorded from WT mice. Under our experimental conditions, it was easier to evoke the mGluR-mediated secondary [Ca(2+)](i) increase in SCA1 PCs. The membrane resistance of SCA1 PCs was 3.3 times higher than that of WT cells, which correlated with the 1.7 times smaller cell body size. Most SCA1 PCs (but not WT) had a delayed onset (about 50--200 ms) to Na(+) spike firing induced by current injection. This delay was increased by hyperpolarizing prepulses and was eliminated by 4-aminopyridine, which suggests that this delay was due to enhancement of the A-like K(+) conductance in the SCA1 PCs. In response to CF stimulation, most PCs in mutant and WT mice had rapid, widespread [Ca(2+)](i) changes that recovered in <200 ms. Some SCA1 PCs showed a slow, localized, secondary Ca(2+) transient following the initial CF Ca(2+) transient, which may reflect release of Ca(2+) from intracellular stores. Thus, with these exceptions, the basic physiological properties of mutant PCs are similar to those of WT neurons, even with dramatic alteration of their morphology and downregulation of Ca(2+) handling molecules.


Assuntos
Cálcio/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Proteínas Nucleares/fisiologia , Células de Purkinje/fisiologia , Potenciais de Ação/fisiologia , Animais , Ataxina-1 , Ataxinas , Cálcio/metabolismo , Tamanho Celular , Dendritos/metabolismo , Impedância Elétrica , Eletrofisiologia , Membranas Intracelulares/metabolismo , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos/genética , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Concentração Osmolar , Células de Purkinje/citologia , Tempo de Reação , Valores de Referência , Sódio/metabolismo , Sódio/fisiologia , Sinapses/fisiologia
9.
Hum Mol Genet ; 10(1): 25-30, 2001 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11136710

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by the expansion of a polyglutamine tract within the SCA1 product, ataxin-1. Previously, using transgenic mice, it was demonstrated that in order for a mutant allele of ataxin-1 to cause disease it must be transported to the nucleus of the neuron. Using an in vitro RNA-binding assay, we demonstrate that ataxin-1 does bind RNA and that this binding diminishes as the length of its polyglutamine tract increases. These observations suggest that ataxin-1 plays a role in RNA metabolism and that the expansion of the polyglutamine tract may alter this function.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Peptídeos/metabolismo , RNA/metabolismo , Ataxias Espinocerebelares/metabolismo , Ataxina-1 , Ataxinas , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Humanos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Plasmídeos/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Transcrição Gênica
11.
Nature ; 408(6808): 101-6, 2000 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-11081516

RESUMO

A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.


Assuntos
Degeneração Neural/genética , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Proteínas Nucleares/genética , Ataxias Espinocerebelares/genética , Animais , Animais Geneticamente Modificados , Ataxina-1 , Ataxinas , Modelos Animais de Doenças , Drosophila , Feminino , Resposta ao Choque Térmico/genética , Humanos , Corpos de Inclusão , Masculino , Doenças Neurodegenerativas/patologia , Fenótipo , Dobramento de Proteína , Retina/metabolismo , Ataxias Espinocerebelares/patologia
12.
Hum Mol Genet ; 9(15): 2305-12, 2000 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-11001934

RESUMO

Expansion of a polyglutamine tract within ataxin-1 causes spinocerebellar ataxia type 1 (SCA1). In this study, we used the yeast two-hybrid system to identify an ataxin-1-interacting protein, A1Up. A1Up localized to the nucleus and cytoplasm of transfected COS-1 cells. In the nucleus, A1Up co-localized with mutant ataxin-1, further demonstrating that A1Up interacts with ataxin-1. Expression analyses demonstrated that A1U mRNA is widely expressed as an approximately 4.0 kb transcript and is present in Purkinje cells, the primary site of SCA1 cerebellar pathology. Sequence comparisons revealed that A1Up contains an N-terminal ubiquitin-like (UbL) region, placing it within a large family of similar proteins. In addition, A1Up has substantial homology to human Chap1/Dsk2, a protein that binds the ATPase domain of the HSP70-like Stch protein. These results suggest that A1Up may link ataxin-1 with the chaperone and ubiquitin-proteasome pathways. In addition, these data support the concept that ataxin-1 may function in the formation and regulation of multimeric protein complexes within the nucleus.


Assuntos
Proteínas de Transporte , Proteínas de Ciclo Celular/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ubiquitinas/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Ataxina-1 , Ataxinas , Proteínas Relacionadas à Autofagia , Northern Blotting , Encéfalo/metabolismo , Células COS , Imunofluorescência , Humanos , Hibridização In Situ , Camundongos , Dados de Sequência Molecular , Especificidade de Órgãos , Ligação Proteica , RNA Mensageiro/análise , Homologia de Sequência de Aminoácidos , Técnicas do Sistema de Duplo-Híbrido
13.
Annu Rev Neurosci ; 23: 217-47, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10845064

RESUMO

A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.


Assuntos
Glutamina/genética , Doenças Neurodegenerativas/genética , Animais , Humanos , Doença de Huntington/genética , Transtornos Musculares Atróficos/genética , Peptídeos/metabolismo , Sequências Repetitivas de Aminoácidos , Ataxias Espinocerebelares/genética
14.
Neurobiol Dis ; 7(3): 129-34, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10860780

RESUMO

Polyglutamine neurodegenerative disorders are characterized by the expansion of a glutamine tract within the mutant disease-causing protein. Expression of the mutant protein induces a progressive loss of neuronal function and the subsequent neurodegeneration of a set of neurons characteristic to each disease. Spinocerebellar ataxia type 1 (SCA1) is one polyglutamine disease where various experimental model systems, in particular transgenic mice, have been utilized to dissect the molecular and cellular events important for disease. This review summarizes these findings and places them in a context of potential future research directions.


Assuntos
Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Proteínas Nucleares/genética , Peptídeos/genética , Ataxias Espinocerebelares/genética , Animais , Ataxina-1 , Ataxinas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos/genética , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia
16.
Hum Mol Genet ; 9(5): 779-85, 2000 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-10749985

RESUMO

To elucidate the pathophysiology of spinocerebellar ataxia type 1 (SCA1) and to evaluate repeat length instability in the context of the mouse Sca1 gene, we generated knock-in mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion show intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. The majority of changes transmitted through the female germline were small contractions, as in humans, whereas small expansions occurred more frequently in paternal transmission. The frequency of intergenerational changes was age dependent for both paternal and maternal transmissions. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wild-type littermates at 9 months of age, although they were not ataxic by cage behavior. Histological examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathological changes observed in other transgenic models overexpressing expanded polyglutamine tracts. These data suggest that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurological phenotype reminiscent of human SCA1. Pathogenesis is thus a function of polyglutamine length, protein levels and duration of neuronal exposure to the mutant protein.


Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Repetições de Trinucleotídeos , Sequência de Aminoácidos , Animais , Ataxina-1 , Ataxinas , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , DNA , Feminino , Impressão Genômica , Humanos , Camundongos , Dados de Sequência Molecular , Fenótipo , Homologia de Sequência do Ácido Nucleico
17.
J Neuropathol Exp Neurol ; 59(4): 265-70, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10759181

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene. One of the major cell types affected by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinje cell. Targeted expression of mutant ataxin-1 in Purkinje cells of transgenic mice produces an ataxic phenotype with pathological similarities to the human disease. Other transgenic experiments using altered forms of mutant ataxin-1 have shown that nuclear localization of the mutant protein is necessary for pathogenesis and that nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and other polyglutamine diseases, are not a requirement for pathogenesis in transgenic models of SCA1. Present and future generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related disorders.


Assuntos
Modelos Animais de Doenças , Doenças Neurodegenerativas/patologia , Peptídeos/genética , Ataxias Espinocerebelares/patologia , Animais , Ataxina-1 , Ataxinas , Encéfalo/patologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Núcleo Celular/ultraestrutura , Cerebelo/patologia , Cerebelo/ultraestrutura , Nervos Cranianos/patologia , Humanos , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Atrofias Olivopontocerebelares/patologia , Células de Purkinje/patologia , Células de Purkinje/ultraestrutura , Medula Espinal/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
18.
Nat Neurosci ; 3(2): 157-63, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10649571

RESUMO

The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occurred before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.


Assuntos
Sistema X-AG de Transporte de Aminoácidos , Regulação para Baixo/genética , Neurônios/enzimologia , Peptídeos/genética , Ataxias Espinocerebelares/genética , Simportadores , Expansão das Repetições de Trinucleotídeos/genética , Animais , Ataxina-1 , Ataxinas , Encéfalo/enzimologia , Canais de Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Clonagem Molecular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteínas de Transporte de Glutamato da Membrana Plasmática , Humanos , Receptores de Inositol 1,4,5-Trifosfato , Inositol Polifosfato 5-Fosfatases , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso , Proteínas Nucleares , Especificidade de Órgãos , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Metiltransferases/biossíntese , Proteínas Metiltransferases/química , Proteínas Metiltransferases/genética , Células de Purkinje/enzimologia , RNA Mensageiro/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Glutamato/metabolismo , Transdução de Sinais/genética , Ataxias Espinocerebelares/etiologia , Ataxias Espinocerebelares/metabolismo , Canais de Cátion TRPC , alfa 1-Antiquimotripsina/metabolismo
19.
Curr Opin Neurobiol ; 9(5): 566-70, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10508741

RESUMO

Neuronal aggregates of the disease-causing protein, often in the nucleus of affected cells, are a pathological hallmark of the neurodegenerative diseases known as polyglutamine disorders. It was suggested that these nuclear aggregates are the cause of these disorders. However, recent evidence suggests that the aggregates, in fact, are not the pathogenic basis and, instead, may play a role in sequestration of the pathogenic protein.


Assuntos
Doenças Neurodegenerativas/metabolismo , Peptídeos/fisiologia , Animais , Caspases/metabolismo , Núcleo Celular/metabolismo , Doenças Neurodegenerativas/etiologia , Peptídeos/química
20.
Philos Trans R Soc Lond B Biol Sci ; 354(1386): 1079-81, 1999 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-10434309

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, transgenic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxia and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear milieu is thus a critical factor in SCA1 pathogenesis, but large NIs are not needed to initiate pathogenesis. They might instead be downstream of the primary pathogenic steps. Given the accumulated evidence, we propose the following model for SCA1 pathogenesis: expansion of the polyglutamine tract alters the conformation of ataxin-1, causing it to misfold. This in turn leads to aberrant protein interactions. Cell specificity is determined by the cell-specific proteins interacting with ataxin-1. Submicroscopic protein aggregation might occur because of protein misfolding, and those aggregates become detectable as NIs as the disease advances. Proteasome redistribution to the NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.


Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Animais , Ataxina-1 , Ataxinas , Tronco Encefálico/patologia , Cerebelo/patologia , Células HeLa , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Camundongos , Camundongos Transgênicos , Peptídeos/genética , Células de Purkinje/patologia , Degenerações Espinocerebelares/fisiopatologia , Transfecção , Repetições de Trinucleotídeos
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