Biomedical subjects

Y Chai

Publications and source records attributed to Y Chai.

At least 19 recordsLinked to original sources

PubMed2003

TGF-beta signaling and its functional significance in regulating the fate of cranial neural crest cells.

Members of the transforming growth factor-beta (TGF-beta) superfamily regulate cell proliferation, differentiation, and apoptosis, and control the development and maintenance of most tissues. TGF-beta signal is transmitted through the phosphorylation of Smad proteins by TGF-beta receptor serine/threonine kinase. During craniofacial development, TGF-beta may regulate the fate specification of cranial neural crest cells. These cells are multipotent progenitors and capable of producing diverse cell types upon differentiation. Here we summarize evidence that TGF-beta ligands and their signaling intermediates have significant roles in patterning and specification of cranial neural crest cells. The biological function of TGF-beta is carried out through the regulation of transcriptional factors during embryogenesis.

Animals↗

PubMed2001

The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease.

Intracellular inclusions are a unifying feature of polyglutamine (polyQ) neurodegenerative diseases, yet each polyQ disease displays a unique pattern of neuronal degeneration. This implies that the protein context of expanded polyQ plays an important role in establishing selective neurotoxicity. Here, in studies of the spinocerebellar ataxia type 3 disease protein ataxin-3, we demonstrate that the protein sequence surrounding polyQ specifies the constituents of nuclear inclusions (NI) formed by the disease protein. The nuclear proteins cAMP response element-binding protein-binding protein (CBP) and Mastermind-like-1 strongly colocalize only to NI formed by full-length ataxin-3, whereas the splicing factor SC35 colocalizes only to NI formed by a polyQ-containing, carboxyl-terminal fragment of ataxin-3. These differences in NI formation reflect specific protein interactions normally undertaken by ataxin-3, as both normal and mutant full-length ataxin-3 co-immunoprecipitate with CBP and sediment on density gradients as macromolecular complexes. Moreover, normal ataxin-3 represses cAMP response element-binding protein-mediated transcription, indicating a functional consequence of ataxin-3 interactions with CBP. Finally, we show that mutant ataxin-3 forms insoluble intranuclear complexes, or microaggregates, before NI can be detected, implying a precursor-product relationship. These results suggest that protein context-dependent recruitment of nuclear proteins to intranuclear microaggregates, and subsequently to NI, may contribute to selective neurotoxicity in polyQ diseases.

Ataxin-3↗

PubMed2001

Antagonistic effects of Smad2 versus Smad7 are sensitive to their expression level during tooth development.

Members of the transforming growth factor-beta (TGF-beta) superfamily regulate cell proliferation, differentiation, and apoptosis, controlling the development and maintenance of most tissues. TGF-beta signal is transmitted through the phosphorylation of Smad proteins by TGF-beta receptor serine/threonine kinase. During early tooth development, TGF-beta inhibits proliferation of enamel organ epithelial cells but the underlying molecular mechanisms are largely unknown. Here we tested the hypothesis that antagonistic effects between Smad2 and Smad7 regulate TGF-beta signaling during tooth development. Attenuation of Smad2 gene expression resulted in significant advancement of embryonic tooth development with increased proliferation of enamel organ epithelial cells, while attenuation of Smad7 resulted in significant inhibition of embryonic tooth development with increased apoptotic activity within enamel organ epithelium. These findings suggest that different Smads may have differential activities in regulating TGF-beta-mediated cell proliferation and death. Furthermore, functional haploinsufficiency of Smad2, but not Smad3, altered TGF-beta-mediated tooth development. The results indicate that Smads are critical factors in orchestrating TGF-beta-mediated gene regulation during embryonic tooth development. The effectiveness of TGF-beta signaling is highly sensitive to the level of Smad gene expression.

Animals↗

PubMed2001

Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-beta-mediated epidermal homeostasis.

Members of the transforming growth factor-beta (TGF-beta) superfamily are critical regulators for epithelial growth and can alter the differentiation of keratinocytes. Transduction of TGF-beta signaling depends on the phosphorylation and activation of Smad proteins by heteromeric complexes of ligand-specific type I and II receptors. To understand the function of TGF-beta and activin-specific Smad, we generated transgenic mice that overexpress Smad2 in epidermis under the control of keratin 14 promoter. Overexpression of Smad2 increases endogenous Smad4 and TGF-beta 1 expression while heterozygous loss of Smad2 reduces their expression levels, suggesting a concerted action of Smad2 and -4 in regulating TGF-beta signaling during skin development. These transgenic mice have delayed hair growth, underdeveloped ears, and shorter tails. In their skin, there is severe thickening of the epidermis with disorganized epidermal architecture, indistinguishable basement membrane, and dermal fibrosis. These abnormal phenotypes are due to increased proliferation of the basal epidermal cells and abnormalities in the program of keratinocyte differentiation. The ectodermally derived enamel structure is also abnormal. Collectively, our study presents the first in vivo evidence that, by providing an auto-feedback in TGF-beta signaling, Smad2 plays a pivotal role in regulating TGF-beta-mediated epidermal homeostasis.

Animals↗

PubMed2001

c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b-mediated growth suppression in breast cancer cells.

Elk-1, a c-Fos protooncogene regulator, which belongs to the ETS-domain family of transcriptional factors, plays an important role in the induction of immediate early gene expression in response to a variety of extracellular signals. In this study, we demonstrate for the first time the in vitro and in vivo interaction of Elk-1 with BRCA1 splice variants BRCA1a and BRCA1b using GST-pull down assays, co-imunoprecipitations/Western blot analysis of cell extracts from breast cancer cells and mammalian two-hybrid assays. We have localized the BRCA1 interaction domain of Elk-1 protein to the conserved ETS domain, a motif involved in DNA binding and protein-protein interactions. We also observed binding of BRCA1 proteins to other ETS-domain transcription factors SAP1, ETS-1, ERG-2 and Fli-1 but not to Elk-1 splice variant DeltaElk-1 and c-Fos protooncogene. Both BRCA1a and BRCA1b splice variants function as growth suppressors of human breast cancer cells. Interestingly, our studies reveal that although both Elk-1 and SAP-1 are highly homologous members of a subfamily of ETS domain proteins called ternary complex factors, it is only Elk-1 but not SAP-1 that can augment the growth suppressive function of BRCA1a/1b proteins in breast cancer cells. Thus Elk-1 could be a potential downstream target of BRCA1 in its growth control pathway. Furthermore, we have observed inhibition of c-Fos promoter activity in BRCA1a transfected stable breast cancer cells and over expression of BRCA1a/1b attenuates MEK-induced SRE activation in vivo. These results demonstrate for the first time a link between the growth suppressive function of BRCA1a/1b proteins and signal transduction pathway involving Elk-1 protein. All these results taken together suggest that one of the mechanisms by which BRCA1a/1b proteins function as growth/tumor suppressors is through inhibition of the expression of Elk-1 target genes like c-Fos.

Alternative Splicing↗

PubMed2001

Glial cell line-derived neurotrophic factor promotes survival and induces differentiation through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathway respectively in PC12 cells.

PC12-GFRalpha1 cells, a clonal cell line engineered to express glial cell line-derived neurotrophic factor receptor alpha1 were constructed. Given glial cell line-derived neurotrophic factor could induce the differentiation and promote the survival of PC12-GFRalpha1 cells at low concentrations, the cells provide an unlimited source of monoclonal cells for studies on the signal transduction pathway of glial cell line-derived neurotrophic factor. To characterize the involvement of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in the biological effect of glial cell line-derived neurotrophic factor, we used the mitogen-activated protein kinase kinase inhibitor PD98059 and the phosphatidylinositol 3-kinase inhibitor LY294002. PD98059 blocked glial cell line-derived neurotrophic factor-induced PC12-GFRalpha1 cells neurite formation in a dose-dependent manner, without significantly altering cell viability. LY294002 reversed the survival-promoting effect of glial cell line-derived neurotrophic factor on the PC12-GFRalpha1 cells in serum-deprived medium. The present study demonstrates that phosphatidylinositol 3-kinase pathway seems to mediate the survival-promoting effect of glial cell line-derived neurotrophic factor on PC12-GFRalpha1 cells, while the activation of mitogen-activated protein kinase pathway could be an important step in mediating PC12-GFRalpha1 cells differentiation induced by glial cell line-derived neurotrophic factor. Therefore, it is inferred that similar intracellular signaling components are used by distinct growth factors toward a common biological effect.

Animals↗

PubMed2001

Impact of nonpenetrating clips on intimal hyperplasia of vascular anastomoses.

Non-penetrating, arcuate-legged titanium clips create an interrupted, non-penetrated, yet compliant vascular anastomoses that is associated with significantly reduced anastomotic neointimal hyperplasia. Recent experimental and clinical studies provide evidence that the non-suture alternative changes the biology of vessel-to-vessel and graft-to-vessel connections that reduces the stimulus for hyperplasia at a number of critical points in the response to injury schema. The compliant, "blood-tight" characteristics of clipped vascular reconstructions are associated with no endothelial injury or intraluminal foreign body, minimal platelet aggregation and laminal flow. Clinical applications including vascular access, femoropopliteal bypass, and closure of carotid endarterectomies are remarkable for the absence of restenosis and preserved anastomotic patency.

Anastomosis, Surgical↗

PubMed2001

TrlR, a defective TraR-like protein of Agrobacterium tumefaciens, blocks TraR function in vitro by forming inactive TrlR:TraR dimers.

Octopine-type Ti plasmids of Agrobacterium tumefaciens require the quorum-sensing proteins TraR and TraI and the diffusible pheromone 3-oxooctanoyl homoserine lactone (AAI) to regulate genes required for conjugal transfer. TraR activity is inhibited by a protein called TrlR, which closely resembles amino acids 1-181 of TraR but is truncated as a result of a shift in the reading frame at codon 182. This frameshift does not affect synthesis of the amino-terminal domain, which is thought to bind autoinducer and mediate protein dimerization, but abolishes translation of the carboxyl-terminal, DNA-binding domain. In this study, we show that TrlR, like TraR, requires AAI for solubility when overexpressed in Escherichia coli. TrlR bound one molecule of AAI per protein monomer, supporting the prediction that the amino-terminal domain of TraR contains the AAI binding site. Purified TrlR blocked TraR for both specific DNA binding and transcription of a tra promoter, supporting previous studies performed with whole cells. When TrlR and a TraR fusion protein were co-expressed in E. coli, these proteins readily formed heterodimeric complexes that were inactive in DNA-binding activity. These data support the hypotheses that (i) the amino-terminal half of TraR binds AAI and mediates protein dimerization; (ii) both DNA-binding domains in a TraR dimer are required for stable DNA binding; and (iii) TrlR blocks TraR by direct protein-protein interactions.

4-Butyrolactone↗

PubMed2001

Prenatal exposure to nitrofen induces Fryns phenotype in mice.

Prenatal exposure to nitrofen is known to cause multiple malformations in mice. The reported malformations include lung hypoplasia, diaphragmatic hernia, cardiovascular defects, skeletal malformations, cleft palate, and renal abnormalities. The authors present detailed findings of craniofacial defects after prenatal exposure to nitrofen, and propose that together with the previously reported malformations, nitrofen exposure induces a Fryns phenotype in mice. Fryns syndrome is a rare human genetic syndrome that is an autosomal recessive disorder characterized by lung hypoplasia, diaphragmatic hernia, craniofacial malformations, skeletal malformations, cardiovascular malformations, and genitourinary malformations. Timed-pregnant Swiss Webster mice were gavage-fed 25 mg of nitrofen on day 8 of gestation. Control animals received olive oil. Osteogenesis and chondrogenesis were studied in fetuses recovered on day 17 after Alcian blue-Alizarin red staining. Approximately 26% of the nitrofen-exposed embryos had severe craniofacial defects, and there was generalized delay in chondrogenesis and osteogenesis throughout the skeleton. No such defects were noted in the control group. The authors propose that prenatal exposure to nitrofen induces a Fryns phenotype in mice, and thus speculate that nitrofen may target similar molecular mechanisms to those that lead to Fryns syndrome.

Abnormalities, Drug-Induced↗

PubMed2001

Diagnosis and treatment of spinal fractures combined with paraplegia and diaphragm injury.

OBJECTIVE: To study the mechanism and treatment principle of spinal fractures combined with paraplegia and diaphragm injury. METHODS: A total of 16 patients (14 males and 2 females, aged from 18 to 50 years) with spinal fractures combined with paraplegia and diaphragm injury, receiving emergency treatment and admitted to our hospital in the past 20 years, were retrospectively analyzed in this study. RESULTS: The injuries were caused by direct or indirect violence. Six cases were of fractures of cervical spine combined with paraplegia and diaphragm injury, 2 of fractures of thoracic vertebra combined with paraplegia and diaphragm injury, and 8 of thoracolumbar fractures combined with paraplegia and diaphragm injury. Six cases received non-operative treatment, but died finally. Ten cases received spine surgical treatment, of which 4 died and 6 were improved. The total mortality rate was 62.5%. CONCLUSIONS: Spinal fractures combined with paraplegia and diaphragm injury are one of the most severe traumas in departments of orthopaedics. Paraplegia can be found easily, but diaphragm injury is often neglected and missed. When a patient suffers from both of them, he is in danger of death. What measures should be taken to rescue the patient's life depends on the severity of the wounds.

Adolescent↗

PubMed2000

CREB-binding protein sequestration by expanded polyglutamine.

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.

Animals↗

PubMed2000

Regulation of cell growth by oxidized LDL.

The first reports of the influences of oxidized LDL (oxLDL) on cell function pertained to negative effects on cell growth-growth arrest, injury, and toxicity. Since these studies, it has become apparent that sublethal levels of oxLDL cause some, but not all, cells to proliferate. This review highlights the growth-promoting effects of oxLDL rather than its inhibitory or injurious effects. Smooth muscle cells (SMCs) and monocyte-macrophages proliferate after exposure to oxLDL; endothelial cells do not. Scavenger receptors are involved in the proliferative effects on monocyte-macrophages, whereas the effects of oxLDL on SMCs appear to be receptor independent. Lysophosphatidylcholine (lysoPC), and structurally related lipids are among the growth-promoting constituents of oxLDL. OxLDL exerts at least a part of its effects by inducing expression or causing the release of growth factors. OxLDL (or lysoPC) can cause the release of basic fibroblast growth factor (bFGF) from SMCs; oxLDL (or lysoPC) can induce heparin binding EGF-like growth factor (HB-EGF) synthesis and release from macrophages. An imposing array of changes in cytokine and growth factor expression and/or release can be imposed by oxLDL on a wide variety of cell types. These effects and the studies probing the cell signaling events leading to them are described.

Animals↗

PubMed2000

Separation and determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation by capillary zone electrophoresis.

A capillary zone electrophoresis method was developed for the separation and determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation. The factors that could affect the separation were studied, such as the types and concentrations of electrolytes, pH, ionic strength and organic modifier. The optimum running buffer was 20 mmol/L of ammonium acetate containing 0.2 mol/L of glacial acetic acid (pH 3.64). The applied voltage was 25 kV and the wavelength of the UV detector was set at 214 nm. The established method with dopamine hydrochloride as internal standard was linear in the range of 5-100 microg/mL for both strychnine and brucine. The recovery was 102.96% for strychnine and 98.56% for brucine. The extracts of Strychnos nux-vomica and its preparation could be directly injected for analysis.

Buffers↗

PubMed2000

Smad7 is a TGF-beta-inducible attenuator of Smad2/3-mediated inhibition of embryonic lung morphogenesis.

Smad7 was recently shown to antagonize TGF-beta-induced activation of signal-transducing Smad2 and Smad3 proteins. However, the biological function of Smad7 in the process of lung organogenesis is not known. Since Smad2/3-mediated TGF-beta signaling is known to inhibit embryonic lung branching morphogenesis, we tested the hypothesis that Smad7 regulates early lung development by modulating TGF-beta signal transduction. An antisense oligodeoxynucleotide (ODN) was designed to specifically block endogenous Smad7 gene expression at both transcriptional and translational levels in embryonic mouse lungs in culture. TGF-beta-mediated inhibition of lung branching morphogenesis was significantly potentiated in cultured embryonic lungs in the absence of Smad7 gene expression: abrogation of Smad7 potentiated TGF-beta-mediated inhibition of lung branching morphogenesis from 76 to 52% of the basal level in lungs cultured in the presence of 5 ng/ml TGF-beta1 ligand. Likewise, TGF-beta1 EC(50) (concentration of TGF-beta1 that induced half maximal branching inhibition) was reduced from 5 to 1 ng/ml when Smad7 gene expression was abrogated in lung culture, indicating an enhanced level of TGF-beta signaling in lung tissue with abolished Smad7 gene expression. By immunocytochemistry, Smad7 protein was co-localized with both Smad2 and Smad3 in distal bronchial epithelial cells, supporting the concept that Smad7 inhibits TGF-beta signaling by competing locally with Smad2 and Smad3 for TGF-beta receptor complex binding during lung morphogenesis. Furthermore, antisense Smad7 ODN increased the negative effect of TGF-beta1 on epithelial cell growth in developing lungs in culture. We also demonstrated that Smad7 mRNA levels were rapidly and potently induced upon TGF-beta1 stimulation of lungs in culture, suggesting that Smad7 regulates TGF-beta responses in a negative feedback loop. These studies define a novel function for Smad7 as an intracellular antagonist of TGF-beta-induced, Smad2/3-mediated inhibition of murine embryonic lung growth and branching morphogenesis in culture. The optimization of TGF-beta signaling during early lung development therefore requires a finely-regulated competitive balance between both permissive and inhibitory members of the Smad family.

Animals↗

PubMed2000

Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.

Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts. The genetic defect in DM is a CTG repeat expansion located in the 3' untranslated region of DMPK and 5' of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5). There are three mechanisms by which CTG expansion can result in DM. First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3' of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10,11). Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted. Our results demonstrate that the rate and severity of cataract formation is inversely related to Six5 dosage and is temporally progressive. Six5+/- and Six5-/- mice show increased steady-state levels of the Na+/K+-ATPase alpha-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM. Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5.

Animals↗

PubMed2000

Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis.

Neural crest cells are multipotential stem cells that contribute extensively to vertebrate development and give rise to various cell and tissue types. Determination of the fate of mammalian neural crest has been inhibited by the lack of appropriate markers. Here, we make use of a two-component genetic system for indelibly marking the progeny of the cranial neural crest during tooth and mandible development. In the first mouse line, Cre recombinase is expressed under the control of the Wnt1 promoter as a transgene. Significantly, Wnt1 transgene expression is limited to the migrating neural crest cells that are derived from the dorsal CNS. The second mouse line, the ROSA26 conditional reporter (R26R), serves as a substrate for the Cre-mediated recombination. Using this two-component genetic system, we have systematically followed the migration and differentiation of the cranial neural crest (CNC) cells from E9.5 to 6 weeks after birth. Our results demonstrate, for the first time, that CNC cells contribute to the formation of condensed dental mesenchyme, dental papilla, odontoblasts, dentine matrix, pulp, cementum, periodontal ligaments, chondrocytes in Meckel's cartilage, mandible, the articulating disc of temporomandibular joint and branchial arch nerve ganglia. More importantly, there is a dynamic distribution of CNC- and non-CNC-derived cells during tooth and mandibular morphogenesis. These results are a first step towards a comprehensive understanding of neural crest cell migration and differentiation during mammalian craniofacial development. Furthermore, this transgenic model also provides a new tool for cell lineage analysis and genetic manipulation of neural-crest-derived components in normal and abnormal embryogenesis.

Animals↗

PubMed2000

Secondary near-pentaploidy and/or near-tetraploidy characterized by the duplication of 8;21 translocation in the M2 subtype of acute myeloid leukemia.

Hyperploidy, especially near-tetraploidy, is rare in acute myeloid leukemia (AML). We report 2 cases with secondary hyperploidy characterized by double 8;21 translocations. Morphologic observation of bone marrow smears revealed numerous giant blasts in both cases. Chromosome analyses with R-banding technique showed a karyotype of 46,XX,t(8;21)(2%)/92,XXXX, add(7)(q31)x2,t(8;21)x2(7%)/100-117,XXX,-X,-X,-1,+4,+4,-7,+add(7)(q31)x3 , t(8;21)x2,+der(21)t(8;21),+22(90.6%)/46,XX(0.3%) in case 1 and a karyotype of 45,X,-Y,t(8;21)(15%)/90,XX,-Y,-Y,t(8;21)x2(80%)/46,XY(5%) in case 2. DNA ploidy analyses by flow cytometry showed triple peaks (diploid, tetraploid [DI 2.09] and near-pentaploid [DI 2.59]) in case 1, and double peaks (diploid and near-tetraploid [DI 2.07]) in case 2. Reverse-transcriptase polymerase chain reaction detected an AML1/ETO fusion transcript (152 bp) in both cases. This paper brings the total number of cases of secondary hyperploid t(8;21) AML to 6 and further emphasizes a correlation between hyperploidy and t(8;21) translocation.

Bone Marrow↗

PubMed1999

Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease.

Polyglutamine (polygln) diseases are a group of inherited neurodegenerative disorders characterized by protein misfolding and aggregation. Here, we investigate the role in polygln disease of heat shock proteins (Hsps), the major class of molecular chaperones responsible for modulating protein folding in the cell. In transfected COS7 and PC12 neural cells, we show that Hsp40 and Hsp70 chaperones localize to intranuclear aggregates formed by either mutant ataxin-3, the disease protein in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), or an unrelated green fluorescent protein fusion protein containing expanded polygln. We further demonstrate that expression of expanded polygln protein elicits a stress response in cells as manifested by marked induction of Hsp70. Studies of SCA3/MJD disease brain confirm these findings, showing localization of Hsp40 and, less commonly, Hsp70 chaperones to intranuclear ataxin-3 aggregates. In transfected cells, overexpression of either of two Hsp40 chaperones, the DNAJ protein homologs HDJ-1 and HDJ-2, suppresses aggregation of truncated or full-length mutant ataxin-3. Finally, we extend these studies to a PC12 neural model of polygln toxicity in which we demonstrate that overexpression of HDJ-1 suppresses polygln aggregation with a parallel decrease in toxicity. These results suggest that expanded polygln protein induces a stress response and that specific molecular chaperones may aid the handling of misfolded or aggregated polygln protein in neurons. This study has therapeutic implications because it suggests that efforts to increase chaperone activity may prove beneficial in this class of diseases.

Animals↗