Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CAG repeats are present in numerous human transcripts but neither their structures nor physiological functions have been satisfactorily recognized. The expanded CAG repeats are present in transcripts from several mutant genes associated with hereditary neurodegenerative diseases but their contribution to pathogenesis has not been documented convincingly. Here, we show that the structures formed by the repeats and their natural flanking sequences in the spinocerebellar ataxia (SCA) type 3 and type 6, and dentatorubral-palidoluysian atrophy (DRPLA) transcripts have different molecular architectures which may have functional meaning. We provide evidence that the hairpin structure formed by CAG repeats in mRNA fragments is preserved in full-length mRNA. We also demonstrate that the single-nucleotide polymorphism (SNP) that is located immediately adjacent (3') to the repeats of the SCA3 transcript modulates the structures formed by these sequences, and may have functional significance, as only one of its variants is selected in human evolution.
J Mol Biol 2004 Jul 16
PMID:Molecular architecture of CAG repeats in human disease related transcripts. 1522 12

Several human neurodegenerative disorders are caused by the expansion of polymorphic trinucleotide repeat regions. Many of these loci are functional short tandem repeats (STRs) located in brain-expressed genes, and their study is thus relevant from both a medical and an evolutionary point of view. The aims of our study are to infer the comparative pattern of variation and evolution of this set of loci in order to show species-specific features in this group of STRs and on their potential for expansion (therefore, an insight into evolutionary medicine) and to unravel whether any human-specific feature may be identified in brain-expressed genes involved in human disease. We analyzed the variability of the normal range of seven expanding STR CAG/CTG loci (SCA1, SCA2, SCA3-MJD, SCA6, SCA8, SCA12, and DRPLA) and two nonexpanding polymorphic CAG loci (KCNN3 and NCOA3) in humans, chimpanzees, gorillas, and orangutans. The study showed a general conservation of the repetitive tract and of the polymorphism in the four species and high heterogeneity among loci distributions. Humans present slightly larger alleles than the rest of species but a more relevant difference appears in variability levels: Humans are the species with the largest variance, although only for the expanding loci, suggesting a relationship between variability levels and expansion potential. The sequence analysis shows high levels of sequence conservation among species, a lack of correspondence between interruption patterns and variability levels, and signs of conservative selective pressure for some of the STR loci. Only two loci (SCA1 and SCA8) show a human specific distribution, with larger alleles than the rest of species. This could account, at the same time, for a human-specific trait and a predisposition to disease through expansion.
J Mol Evol 2004 Sep
PMID:Comparative genetics of functional trinucleotide tandem repeats in humans and apes. 1555 88

The expanded CAG tract diseases are a heterogeneous group of late-onset neurodegenerative disorders characterized by the accumulation of insoluble protein material and premature neuronal cell death. Recent work has provided support for several mechanisms that may account for neurodegeneration, but no unifying mechanism has emerged. We have previously demonstrated that in SCA3, the expanded CAG tract in the MJD-1 transcript is prone to frameshifting, which may lead to the production of polyalanine-containing proteins. To further examine the occurrence of frameshifting and understand its mechanism and possible role in pathogenesis, a cellular model was established. We show that this phenomenon results from ribosomal slippage to the -1 frame exclusively, that ribosomal frameshifting depends on the presence of long CAG tracts and that polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Finally, we present evidence that anisomycin, a ribosome-interacting drug that reduces -1 frameshifting, also reduces toxicity, suggesting a new therapeutic opportunity for these disorders.
Hum Mol Genet 2005 Sep 15
PMID:Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts. 1608 86

Expansion of a polyglutamine tract in ataxin-3 (AT3) results in spinocerebellar ataxia type 3/Machado-Joseph disease, one of the nine polyglutamine neurodegenerative diseases. Understanding the normal functions of AT3 as well as its function in the context of expansion of the polyglutamine tract is critical for understanding the disease process. AT3 is a deubiquitylating enzyme with limited information on its cellular functions. We find that transfecting cells with AT3 increases cellular levels of endoplasmic reticulum-associated degradation (ERAD) substrates, CD3delta and TCRalpha, but does not alter levels of several non-ERAD substrates. AT3 increases the level of CD3delta by decreasing its degradation; pathogenic AT3 decreases degradation to a greater extent than wild-type AT3. Knock-down of endogenous AT3 decreases levels of CD3delta, suggesting that a normal function of AT3 is to regulate levels of ERAD substrates. AT3 binds VCP/p97, a key protein responsible for extracting ERAD substrates from the ER; binding is modulated by the size of the polyglutamine tract, and mutating a sequence adjacent to the polyglutamine tract inhibits the AT3-VCP interaction and AT3-dependent accumulation of CD3delta. AT3 and Ufd1 bind VCP in a mutually exclusive manner; AT3 decreases the interaction of VCP with Ufd1 as well as with ubiquitylated proteins. Using a reconstituted system, AT3 inhibits retrotranslocation of an ERAD substrate from the ER. These data suggest that a normal function of AT3 is to regulate flow through the ERAD pathway by modulating VCP-dependent extraction of proteins from the ER.
Hum Mol Genet 2006 Aug 15
PMID:Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. 1682 50

Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin. Here we show that E2-25K is involved in aggregate formation of expanded polyglutamine proteins and polyglutamine-induced cell death. Both a truncated mutant, lacking the catalytic tail domain, as well as a full antisense sequence, reduce aggregate formation. Strikingly, both E2-25K mutants also reduced polyglutamine-induced cell death. In postmortem brain material of both Huntington disease and SCA3, E2-25K staining of polyglutamine aggregates was observed in a subset of neurons bearing intranuclear neuronal inclusions. These results demonstrate that targeting by ubiquitination plays an important role in the pathology of polyglutamine diseases.
Mol Cell Neurosci 2007 Jan
PMID:Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases. 1709 42

The polyglutamine diseases are a family of nine proteins where intracellular protein misfolding and amyloid-like fibril formation are intrinsically coupled to disease. Previously, we identified a complex two-step mechanism of fibril formation of pathologically expanded ataxin-3, the causative protein of spinocerebellar ataxia type-3 (Machado-Joseph disease). Strikingly, ataxin-3 lacking a polyglutamine tract also formed fibrils, although this occurred only via a single-step that was homologous to the first step of expanded ataxin-3 fibril formation. Here, we present the first kinetic analysis of a disease-associated polyglutamine repeat protein. We show that ataxin-3 forms amyloid-like fibrils by a nucleation-dependent polymerization mechanism. We kinetically model the nucleating event in ataxin-3 fibrillogenesis to the formation of a monomeric thermodynamic nucleus. Fibril elongation then proceeds by a mechanism of monomer addition. The presence of an expanded polyglutamine tract leads subsequently to rapid inter-fibril association and formation of large, highly stable amyloid-like fibrils. These results enhance our general understanding of polyglutamine fibrillogenesis and highlights the role of non-poly(Q) domains in modulating the kinetics of misfolding in this family.
J Mol Biol 2007 Apr 27
PMID:Mechanisms of ataxin-3 misfolding and fibril formation: kinetic analysis of a disease-associated polyglutamine protein. 1736 87

Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.
Mol Cells 2007 Dec 31
PMID:Molecular analysis of CAG repeats at five different spinocerebellar ataxia loci: correlation and alternative explanations for disease pathogenesis. 1818 48

Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.
Hum Mol Genet 2008 Jul 15
PMID:Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease. 1838

Superoxide dismutase-1 (SOD1) and ataxin-3 are two neurodegenerative disease proteins in association with familial amyotrophic lateral sclerosis and Machado-Joseph disease/spinocerebellar ataxia type 3. Both normal and mutant types of SOD1 and ataxin-3 are degraded by the proteasome. It was recently reported that these two proteins are associated with the endoplasmic reticulum (ER). Mammalian gp78 is an E3 ubiquitin ligase involved in ER-associated degradation (ERAD). Here, we show that gp78 interacts with both SOD1 and ataxin-3. Overexpression of gp78 promotes the ubiquitination and degradation of these two proteins, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 and ataxin-3 to target them for ERAD.
Hum Mol Genet 2009 Nov 15
PMID:Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. 1966 Nov 82

Protein cleavage is a common feature in human neurodegenerative disease. Ataxin-3 protein with an expanded polyglutamine (polyQ) repeat causes spinocerebellar ataxia type-3 (SCA3), also called Machado-Joseph disease, and is cleaved in mammalian cells, transgenic mice and SCA3 patient brain tissue. However, the pathological significance of Ataxin-3 cleavage has not been carefully examined. To gain insight into the significance of Ataxin-3 cleavage, we developed a Drosophila SL2 cell-based model as well as transgenic fly models. Our data indicate that Ataxin-3 protein cleavage is conserved in the fly and may be caspase-dependent as reported previously. Importantly, comparison of flies expressing either wild-type or caspase-site mutant proteins indicates that Ataxin-3 cleavage enhances neuronal loss in vivo. This genetic in vivo confirmation of the pathological role of Ataxin-3 cleavage indicates that therapies targeting Ataxin-3 cleavage might slow disease progression in SCA3 patients.
Hum Mol Genet 2009 Dec 15
PMID:Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. 1978 48


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