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Huda Y. Zoghbi - One of the best experts on this subject based on the ideXlab platform.
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purkinje cell ataxin 1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum
The Journal of Neuroscience, 2013Co-Authors: Blake A Ebner, Huda Y. Zoghbi, Lisa A Duvick, Justin Barnes, Melissa A Ingram, Jillian Frisch, Brent H Clark, Timothy J EbnerAbstract:Previous studies indicate that while transgenic mice with ATXN1[30Q]-D776-induced disease share pathological features caused by ATXN1[82Q] having an expanded Polyglutamine Tract, they fail to manifest the age-related progressive neurodegeneration seen in spinocerebellar ataxia type 1. The shared features include morphological alterations in climbing fiber (CF) innervation of Purkinje cells (PCs). To further investigate the ability of ataxin-1 (ATXN1) to impact CF/PC innervation, this study used morphological and functional approaches to examine CF/PC innervation during postnatal development in ATXN1[30Q]-D776 and ATXN1[82Q] cerebella. Notably, ATXN1[30Q]-D776 induced morphological alterations consistent with the development of the innervation of PCs by CFs being compromised, including a reduction of CF translocation along the PC dendritic tree, and decreased pruning of CF terminals from the PC soma. As previously shown for ATXN1[82Q], ATXN1[30Q]-D776 must enter the nucleus of PCs to induce these alterations. Experiments using conditional ATXN1 [ 30Q ]- D776 mice demonstrate that both the levels and specific timing of mutant ATXN1 expression are critical for alteration of the CF–PC synapse. Together these observations suggest that ATXN1, expressed exclusively in PCs, alters expression of a gene(s) in the postsynaptic PC that are critical for its innervation by CFs. To investigate whether ATXN1[30Q]-D776 curbs the progressive disease in ATXN1 [ 82Q ] -S776 mice, we crossed ATXN1 [ 30Q ] -D776 and ATXN1 [ 82Q ] -S776 mice and found that double transgenic mice developed progressive PC atrophy. Thus, the results also show that to develop progressive cerebellar degeneration requires expressing ATXN1 with an expanded Polyglutamine Tract.
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sca1 like disease in mice expressing wild type ataxin 1 with a serine to aspartic acid replacement at residue 776
Neuron, 2010Co-Authors: Lisa A Duvick, Huda Y. Zoghbi, Justin Barnes, Blake A Ebner, Smita Agrawal, Michael J Andresen, Janghoo Lim, Glenn J Giesler, Harry T OrrAbstract:Glutamine Tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here, we show that replacing Ser776 with a phosphomimicking Asp converted ATXN1 with a wild-type glutamine Tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded Polyglutamine Tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the Polyglutamine Tract. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded Polyglutamine Tract is essential for neuronal death.
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pathogenic mechanisms of a Polyglutamine mediated neurodegenerative disease spinocerebellar ataxia type 1
Journal of Biological Chemistry, 2009Co-Authors: Huda Y. ZoghbiAbstract:Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative diseases caused by the expansion of a CAG trinucleotide repeat encoding a Polyglutamine Tract. SCA1 patients lose motor coordination and develop slurred speech, spasticity, and cognitive impairments. Difficulty with coordinating swallowing and breathing eventually causes death. Genetic evidence indicates that the disease mutation induces a toxic gain of function in the SCA1 encoded protein ATXN1. The discovery that residues in ATXN1 outside of the Polyglutamine Tract are crucial for pathogenesis hinted that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the Polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at Ser776 and a subsequent alteration in its interaction with other cellular proteins. Moreover, the finding that other ATXN1 interactions are decreased in disease suggests that the Polyglutamine expansion contributes to disease by both a gain-of-function mechanism and partial loss of function.
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opposing effects of Polyglutamine expansion on native protein complexes contribute to sca1
Nature, 2008Co-Authors: Juan Crespobarreto, Paymaan Jafarnejad, David E. Hill, Ronald Richman, Aaron B. Bowman, Huda Y. ZoghbiAbstract:Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known Polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded Polyglutamine Tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, Polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other Polyglutamine diseases. Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disease caused by faulty insertion of stretches of glutamines in the ataxin1 protein. Just how these 'Polyglutamine expansions' make a protein neurotoxic — in SCA1 and eight other neurodegenerative diseases including Huntington's — is not clear. Lim et al. now show that the expanded Polyglutamine Tract can affect ataxin1 protein function in different ways, depending on the protein partners it associates with. Both loss of function and, more surprisingly, gain of function was observed. Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1. The expanded Polyglutamine Tract can affect the function of the ataxin1 protein in different ways, depending on the protein partners ataxin1 is associated with. This paper shows that Polyglutamine expansion in one and the same protein can cause gain of function and loss of function toxicity at the same time.
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interaction of akt phosphorylated ataxin 1 with 14 3 3 mediates neurodegeneration in spinocerebellar ataxia type 1
Cell, 2003Co-Authors: Michael D Kaytor, Hung Kai Chen, Pedro Fernandezfunez, Summer F Acevedo, Michael H Fernandez, Alastair Aitken, Efthimios M C Skoulakis, Juan Botas, Huda Y. ZoghbiAbstract:Spinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by a CAG repeat expansion. In SCA1, this expansion produces an abnormally long Polyglutamine Tract in the protein ataxin-1. Mutant Polyglutamine proteins accumulate in neurons, inducing neurodegeneration, but the mechanism underlying this accumulation has been unclear. We have discovered that the 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. The association of ataxin-1 with 14-3-3 is regulated by Akt phosphorylation, and in a Drosophila model of SCA1, both 14-3-3 and Akt modulate neurodegeneration. Our finding that phosphatidylinositol 3-kinase/Akt signaling and 14-3-3 cooperate to modulate the neurotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and identifies potential targets for therapeutic intervention.
Hitoshi Okazawa - One of the best experts on this subject based on the ideXlab platform.
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Segmental isotope-labeling of the intrinsically disordered protein PQBP1
FEBS Letters, 2014Co-Authors: Yuko Nabeshima, Asagi Kajiyama, Mineyuki Mizuguchi, Hitoshi OkazawaAbstract:Polyglutamine Tract-binding protein 1 (PQBP1) is an intrinsically disordered protein abundantly expressed in the brain. Mutations in the PQBP1 gene are causative for X-linked mental retardation disorders. Here, we investigated the structure of the C-terminal segment within the context of full-length PQBP1. We produced a segmentally isotope-labeled PQBP1 composed of a non-labeled segment (residues 1–219; N-segment) and a 13C/15N-labeled segment (residues 220–265; C-segment). Our results demonstrate that the segmental isotope-labeling combined with NMR spectroscopy is useful for detecting a very weak intra-molecular interaction in an intrinsically disordered protein.
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solution model of the intrinsically disordered Polyglutamine Tract binding protein 1
Biophysical Journal, 2012Co-Authors: Martin Rees, Hitoshi Okazawa, Christian Gorba, Cesira De Chiara, Tam T T Bui, Mitla Garciamaya, Alex F Drake, Annalisa Pastore, Dmitri I Svergun, Yu Wai ChenAbstract:Polyglutamine Tract-binding protein-1 (PQBP-1) is a 265-residue nuclear protein that is involved in transcriptional regulation. In addition to its role in the molecular pathology of the Polyglutamine expansion diseases, mutations of the protein are associated with X-linked mental retardation. PQBP-1 binds specifically to glutamine repeat sequences and proline-rich regions, and interacts with RNA polymerase II and the spliceosomal protein U5-15kD. In this work, we obtained a biophysical characterization of this protein by employing complementary structural methods. PQBP-1 is shown to be a moderately compact but largely disordered molecule with an elongated shape, having a Stokes radius of 3.7 nm and a maximum molecular dimension of 13 nm. The protein is monomeric in solution, has residual β-structure, and is in a premolten globule state that is unaffected by natural osmolytes. Using small-angle x-ray scattering data, we were able to generate a low-resolution, three-dimensional model of PQBP-1.
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Polyglutamine Tract binding protein 1 binds to u5 15kd via a continuous 23 residue segment of the c terminal domain
Biochimica et Biophysica Acta, 2010Co-Authors: Masaki Takahashi, Hitoshi Okazawa, Mineyuki Mizuguchi, Hiroyuki Shinoda, Tomoyasu Aizawa, Makoto Demura, Keiichi KawanoAbstract:Polyglutamine Tract-binding protein-1 (PQBP-1) is a nuclear protein that interacts with various proteins, including RNA polymerase II and the spliceosomal protein U5-15kD. PQBP-1 is known to be associated with X-linked mental retardation in which a frameshift mutation in the PQBP-1 gene occurs. In the present study, we demonstrate that PQBP-1 binds to U5-15kD via a continuous 23-residue segment within its C-terminal domain. Intriguingly, this segment is lost in the frameshift mutants of PQBP-1 associated with X-linked mental retardation. These findings suggest that the frameshift mutations in the PQBP-1 gene lead to expression of mutants lacking the ability to interact with U5-15kD.
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Polyglutamine Tract binding protein 1 is an intrinsically unstructured protein
Biochimica et Biophysica Acta, 2009Co-Authors: Masaki Takahashi, Hitoshi Okazawa, Mineyuki Mizuguchi, Hiroyuki Shinoda, Tomoyasu Aizawa, Makoto Demura, Keiichi KawanoAbstract:Polyglutamine Tract binding protein-1 (PQBP-1) is a nuclear protein that interacts with disease proteins containing expanded Polyglutamine repeats. PQBP-1 also interacts with RNA polymerase II and a spliceosomal protein U5-15kD. In the present study, we demonstrate that PQBP-1 is composed of a large unstructured region and a small folded core. Intriguingly, the large unstructured region encompasses two functional domains: a polar amino acid rich domain and a C-terminal domain. These findings suggest that PQBP-1 belongs to the family of intrinsically unstructured/disordered proteins. Furthermore, the binding of the target molecule U5-15kD induces only minor conformational changes into PQBP-1. Our results suggest that PQBP-1 includes high content of unstructured regions in the C-terminal domain, in spite of the binding of U5-15kD.
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Polyglutamine Tract binding protein 1 dysfunction induces cell death of neurons through mitochondrial stress
Journal of Neurochemistry, 2005Co-Authors: Shigeki Marubuchi, Hitoshi Okazawa, Ichiro Kanazawa, Yoichi Wada, Tomohiro Okuda, Yukiko Hara, Masataka Hoshino, Masaya NakagawaAbstract:Polyglutamine Tract-binding protein-1 (PQBP-1) is a nuclear protein that interacts and colocalizes with mutant Polyglutamine proteins. We previously reported that PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype and cell death of motor neurons analogous to human neurodegeneration. To investigate the molecular mechanisms underlying the motor neuron death, we performed microarray analyses using the anterior horn tissues of the spinal cord and compared gene expression profiles between pre-symptomatic transgenic and age-matched control mice. Surprisingly, half of the spots changed more than 1.5-fold turned out to be genes transcribed from the mitochondrial genome. Northern and western analyses confirmed up-regulation of representative mitochondrial genes, cytochrome c oxidase (COX) subunit 1 and 2. Immunohistochemistry revealed that COX1 and COX2 proteins are increased in spinal motor neurons. Electron microscopic analyses revealed morphological abnormalities of mitochondria in the motor neurons. PQBP-1 overexpression in primary neurons by adenovirus vector induced abnormalities of mitochondrial membrane potential from day 5, while cytochrome c release and caspase 3 activation were observed on day 9. An increase of cell death by PQBP-1 was also confirmed on day 9. Collectively, these results indicate that dysfunction of PQBP-1 induces mitochondrial stress, a key molecular pathomechanism that is shared among human neurodegenerative disorders.
Taeyang Jung - One of the best experts on this subject based on the ideXlab platform.
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huntingtin s spherical solenoid structure enables Polyglutamine Tract dependent modulation of its structure and function
eLife, 2016Co-Authors: Ravi Vijayvargia, Raquel F Epand, Alexander Leitner, Taeyang Jung, Baehyun Shin, Roy Jung, Alejandro Lloret, Randy Singh AtwalAbstract:The Polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the Polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the Polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the Polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal Polyglutamine Tract confers a novel property on huntingtin, causing the disease.
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huntingtin s spherical solenoid structure enables Polyglutamine Tract dependent modulation of its structure and function
eLife, 2016Co-Authors: Ravi Vijayvargia, Raquel F Epand, Alexander Leitner, Taeyang Jung, Baehyun Shin, Roy Jung, Alejandro Lloret, Randy Singh AtwalAbstract:Huntington’s disease is an inherited disorder that occurs in adulthood and sometimes in children. It causes progressive damage to the brain and people with the condition develop memory loss, movement difficulties, confusion, and other symptoms of mental decline. Eventually, the disease leads to death. Mutations in the gene that encodes a protein called huntingtin cause Huntington’s disease. Individuals who inherit just one copy of the mutated gene develop the condition. No treatments currently exist that can slow or stop disease progression. Genetic and molecular studies are beginning to shed light on how mutations in the gene encoding huntingtin cause the disease. Normally, the protein has a section near its tail end made up of the amino acid glutamine repeated around 23 times. Mutations that increase the number of glutamines to more than 38 cause Huntington’s disease. The more extra glutamines there are in this region of the protein, the earlier in life the disease symptoms begin. But it was not clear how these extra glutamines near the tail of huntingtin affect the structure and behavior of a protein that is more than 3,000 amino acids long. Now, Vijayvargia et al. have revealed why the tail end of huntingtin is so important. Several biophysical methods were used to determine the three-dimensional structure of the huntingtin protein. These methods revealed that the protein folds up into a hollow sphere and that its tail end is able to interact with the entire length of the protein and physically touches its opposite end. To see this in more detail, Vijayvargia et al. used another experimental technique called crosslinking mass spectrometry to confirm which parts of the huntingtin protein are in close contact with each other. Together with the structural data, these experiments suggest that the stretch of glutamines is in the position to bring about subtle, but widespread, changes throughout the huntingtin protein. That is to say, that having more glutamines slightly changes the curve of the sphere and alters the way different parts of the protein interact. Together the new findings explain why mutations that alter the tail of huntingtin affect the rest of the protein. Further work will now aim to provide a more-detailed structure of the huntingtin protein and to investigate what other roles of huntingtin are affected by the increased number of glutamines in the protein’s tail. These insights may help scientists understand how the mutated protein causes brain decline.
Randy Singh Atwal - One of the best experts on this subject based on the ideXlab platform.
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huntingtin s spherical solenoid structure enables Polyglutamine Tract dependent modulation of its structure and function
eLife, 2016Co-Authors: Ravi Vijayvargia, Raquel F Epand, Alexander Leitner, Taeyang Jung, Baehyun Shin, Roy Jung, Alejandro Lloret, Randy Singh AtwalAbstract:Huntington’s disease is an inherited disorder that occurs in adulthood and sometimes in children. It causes progressive damage to the brain and people with the condition develop memory loss, movement difficulties, confusion, and other symptoms of mental decline. Eventually, the disease leads to death. Mutations in the gene that encodes a protein called huntingtin cause Huntington’s disease. Individuals who inherit just one copy of the mutated gene develop the condition. No treatments currently exist that can slow or stop disease progression. Genetic and molecular studies are beginning to shed light on how mutations in the gene encoding huntingtin cause the disease. Normally, the protein has a section near its tail end made up of the amino acid glutamine repeated around 23 times. Mutations that increase the number of glutamines to more than 38 cause Huntington’s disease. The more extra glutamines there are in this region of the protein, the earlier in life the disease symptoms begin. But it was not clear how these extra glutamines near the tail of huntingtin affect the structure and behavior of a protein that is more than 3,000 amino acids long. Now, Vijayvargia et al. have revealed why the tail end of huntingtin is so important. Several biophysical methods were used to determine the three-dimensional structure of the huntingtin protein. These methods revealed that the protein folds up into a hollow sphere and that its tail end is able to interact with the entire length of the protein and physically touches its opposite end. To see this in more detail, Vijayvargia et al. used another experimental technique called crosslinking mass spectrometry to confirm which parts of the huntingtin protein are in close contact with each other. Together with the structural data, these experiments suggest that the stretch of glutamines is in the position to bring about subtle, but widespread, changes throughout the huntingtin protein. That is to say, that having more glutamines slightly changes the curve of the sphere and alters the way different parts of the protein interact. Together the new findings explain why mutations that alter the tail of huntingtin affect the rest of the protein. Further work will now aim to provide a more-detailed structure of the huntingtin protein and to investigate what other roles of huntingtin are affected by the increased number of glutamines in the protein’s tail. These insights may help scientists understand how the mutated protein causes brain decline.
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huntingtin s spherical solenoid structure enables Polyglutamine Tract dependent modulation of its structure and function
eLife, 2016Co-Authors: Ravi Vijayvargia, Raquel F Epand, Alexander Leitner, Taeyang Jung, Baehyun Shin, Roy Jung, Alejandro Lloret, Randy Singh AtwalAbstract:The Polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the Polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the Polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the Polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal Polyglutamine Tract confers a novel property on huntingtin, causing the disease.
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Huntington’s disease: revisiting the aggregation hypothesis in Polyglutamine neurodegenerative diseases
FEBS Journal, 2008Co-Authors: Ray Truant, Carly R. Desmond, Randy Singh Atwal, Lise N Munsie, Thu L. TranAbstract:After the successful cloning of the first gene for a Polyglutamine disease in 1991, the expanded Polyglutamine Tract in the nine Polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington’s disease and other Polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers, and that the protein context of expanded Polyglutamine is critical to understanding disease specificity. Here we discuss recent publications that define other important therapeutic targets for Polyglutamine-mediated neurodegeneration related to the context of the expanded Polyglutamine Tract in the disease protein.
Harry T Orr - One of the best experts on this subject based on the ideXlab platform.
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sca1 like disease in mice expressing wild type ataxin 1 with a serine to aspartic acid replacement at residue 776
Neuron, 2010Co-Authors: Lisa A Duvick, Huda Y. Zoghbi, Justin Barnes, Blake A Ebner, Smita Agrawal, Michael J Andresen, Janghoo Lim, Glenn J Giesler, Harry T OrrAbstract:Glutamine Tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here, we show that replacing Ser776 with a phosphomimicking Asp converted ATXN1 with a wild-type glutamine Tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded Polyglutamine Tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the Polyglutamine Tract. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded Polyglutamine Tract is essential for neuronal death.
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the spinocerebellar ataxia type 1 protein ataxin 1 has rna binding activity that is inversely affected by the length of its Polyglutamine Tract
Human Molecular Genetics, 2001Co-Authors: Shinji Yue, Huda Y. Zoghbi, Heliane G Serra, Harry T OrrAbstract: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.
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Glutamine Repeats and Neurodegeneration
Annual Review of Neuroscience, 2000Co-Authors: Huda Y. Zoghbi, Harry T OrrAbstract: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.