Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The mechanism by which aggregated polygins cause the selective neurodegeneration in Huntington's disease (HD) is unknown. Here, we show that the SH3GL3 protein, which is preferentially expressed in brain and testis, selectively interacts with the HD exon 1 protein (HDex1p) containing a glutamine repeat in the pathological range and promotes the formation of insoluble polyglutamine-containing aggregates in vivo. The C-terminal SH3 domain in SH3GL3 and the proline-rich region in HDex1p are essential for the interaction. Coimmunoprecipitations and immunofluorescence studies revealed that SH3GL3 and HDex1p colocalize in transfected COS cells. Additionally, an anti-SH3GL3 antibody was also able to coimmunoprecipitate the full-length huntingtin from an HD human brain extract. The characteristics of the interaction between SH3GL3 and huntingtin and the colocalization of the two proteins suggest that SH3GL3 could be involved in the selective neuronal cell death in HD.
Mol Cell 1998 Oct
PMID:SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. 980 64

To date, eight neurodegenerative diseases, including Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7, have been proven to be caused by an expanded trinucleotide repeat (CAG)n located within a specific gene for each of these diseases. Except in SCA 6, the CAG repeat is present in approximately 7 to 35 copies in the normal population, whereas patients have CAG expansions of 40 to approximately 75 repeats. Sizing of the repeat length enables molecular diagnosis in affected patients and presymptomatic persons carrying a mutated allele. A molecular protocol for the diagnosis of these diseases was developed based on polymerase chain reaction, denaturing polyacrylamide gel electrophoresis and staining with silver nitrate, and adapted to each disease. This simple and rapid method gives a sensitivity of detection equal to current procedures but avoids isotopic manipulations. Therefore, shorter turnaround time, decreased cost per sample, and simplified screening of these neurodegenerative diseases by PCR-based assays may be attainable using this protocol.
Diagn Mol Pathol 1998 Jun
PMID:Simple nonisotopic assays for detection of (CAG)n repeats expansions associated with seven neurodegenerative disorders. 983 74

The efficacy of treating neurodegenerative diseases with the transplantation of fetal tissue has been demonstrated in animal models of Parkinson's disease, Huntington's disease and stroke. In the clinical setting, neural transplantation as a treatment for patients with Parkinson's disease has shown promising results. However, for this treatment method to be effective neuronal survival needs to be improved through either trophic support or localized immunoprotection. Co-transplanting Sertoli cells, which express many nutritive, regulatory, trophic and immunosuppressive factors, with fetal neural cells could provide both of these requirements. Such a strategy could enhance the recovery benefits associated with transplantation and decrease the need for, and the risks associated with, long-term systemic immunosuppression.
Mol Med Today 1998 Nov
PMID:Sertoli cell transplants: their use in the treatment of neurodegenerative disease. 985 66

The functional imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPET) have been used to study regional brain function in Huntington's disease (HD) in vivo. Reduced striatal glucose metabolism and dopamine receptor binding are evident in all symptomatic HD patients and in approximately 50% of asymptomatic adult mutation carriers. These characteristics correlate with clinical measures of disease severity. Reduced cortical glucose metabolism and dopamine receptor binding, together with reduced striatal and cortical opioid receptor binding, have also been demonstrated in symptomatic patients with HD. Repeat PET measures of striatal function have been used to monitor the progression of this disease objectively. In the future, functional imaging will provide a valuable way of assessing the efficacy of both fetal striatal cell implants and putative neuroprotective agents, such as nerve growth factors.
Mol Med Today 1998 Dec
PMID:Advances in the understanding of early Huntington's disease using the functional imaging techniques of PET and SPET. 986 23

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have lead to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system that compared the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. We first assessed the mode of nuclear transport of N-terminal fragments of huntingtin, and show that the predicted endogenous NLS is not functional, providing data in support of passive nuclear transport. This result suggests that proteolysis is a necessary step for nuclear entry of huntingtin. Additionally, insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. The findings of nuclear and cytoplasmic aggregates in affected brains, together with these in vitro data, support the nucleus and cytosol as subcellular sites for pathogenesis in HD.
Hum Mol Genet 1999 Jan
PMID:In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease. 988 28

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.
Hum Mol Genet 1999 Jan
PMID:Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. 988 39

Trinucleotide repeat disease alleles can undergo 'dynamic' mutations in which repeat number may change when a gene is transmitted from parent to offspring. By typing >3500 sperm, we determined the size distribution of Huntington's disease (HD) germline mutations produced by 26 individuals from the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82% and, for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a mutation process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. In several cases, the mean change in repeat number differed significantly among individuals with similar somatic allele sizes. This individual variation could not be attributed to age in a simple way or to ' cis ' sequences, suggesting the influence of genetic background or other factors. A familial effect is suggested in one family where both the father and son gave highly unusual spectra compared with other individuals matched for age and repeat number. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data but variation in parameter values among individuals suggests that the molecular mechanism might be more complex.
Hum Mol Genet 1999 Feb
PMID:Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism. 993 25

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.
Hum Mol Genet 1999 Mar
PMID:Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. 994 99

Dentatorubral-pallidoluysian atrophy (DRPLA) is known to show the most prominent genetic anticipation among CAG repeat diseases. To investigate the mechanism underlying the meiotic instability of expanded CAG repeats in the gene for DRPLA, we determined the CAG repeat sizes of 427 single sperm from two individuals with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38. 5), Huntington's disease (69.0) and spinal and bulbar muscular atrophy (16.3), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance of the change in CAG repeat size was significantly different between the two DRPLA patients (F-test, P < 0.0001). However, the segregation ratio of single sperm with an expanded allele to ones with a normal allele is not statistically different ( P = 0.161) from the expected 1:1 segregation ratio, and thus segregation distortion of expanded alleles in meiosis in male patients with DRPLA was not demonstrated.
Hum Mol Genet 1999 Mar
PMID:Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases. 994 4

Polyglutamine expansion (PGE) encoded by a CAG repeat underlies eight inherited neurodegenerative diseases, among which is Huntington's disease. CAG expansion has also been reported in schizophrenia, suggesting a role for PGE. To investigate the potential role of PGE as a candidate for schizophrenia, we searched for PGE in nuclear families comprising a patient affected by childhood onset schizophrenia (COS, a rare and severe form of the disease) as a variation of the candidate gene approach for identifying susceptibility genes. We tested lymphoblastoid cell lines from COS patients (n = 32) by Western blot analysis with 1C2, a monoclonal antibody that specifically recognizes long polyglutamines. Eight of 11 unrelated black American COS patients showed a 60-kDa (approximately) band indicative of PGE. A strong 60-kDa band (suggestive of a large PGE) was detected in two of the eight positive patients. A weaker 60-kDa band (suggestive of a smaller and non pathogenic PGE) was detected in some unaffected parents or sibs of these two COS patients, and in six other black American COS patients. The strong and weak PGE signals were found to correspond to two different proteins. Unrelated black Americans unaffected by COS (n = 38) were negative for the strong 60-kDa PGE signal. Healthy white Americans (n = 53) were negative for both the strong and weak 60-kDa PGE signals. Two-dimensional gel analysis suggested that the strong PGE signal corresponds to an acidic (pI 4 approximately) protein and resulted in a more precise estimation (52-57 kDa) of its relative mass. This protein appeared to be not represented in Genbank, as suggested by the exclusion of several candidate CAG repeats. Our data suggest that this acidic protein might be a candidate for COS.
Mol Psychiatry 1999 Jan
PMID:Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia? 1088 23


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