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1.
Br J Clin Pharmacol ; 84(12): 2790-2801, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30079636

RESUMO

AIMS: This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta® ) in healthy subjects. Safety and immunogenicity were also assessed. METHODS: The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period. Healthy subjects aged 18-45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration-time curve (AUC) from time of dosing and extrapolated to infinity (AUC0-inf ), or to the last measurable concentration (AUC0-last ), maximum observed serum concentration (Cmax ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last ) and ANC maximum effect attributable to the therapy under investigation (Emax ) were completely contained within the predefined margin (0.8 to 1.25). RESULTS: Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (0.9737-1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti-drug antibodies. No neutralizing or clinically relevant antibodies were detected. CONCLUSIONS: PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.


Assuntos
Medicamentos Biossimilares/farmacocinética , Filgrastim/farmacocinética , Polietilenoglicóis/farmacocinética , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Filgrastim/efeitos adversos , Filgrastim/imunologia , Filgrastim/farmacologia , Voluntários Saudáveis , Humanos , Masculino , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia
2.
Am J Nephrol ; 46(5): 364-370, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29084409

RESUMO

BACKGROUND: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia. METHODS: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28). RESULTS: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was -0.093 g/dL, with 90% CI (-0.23 to 0.04) entirely within the pre-specified equivalence limits (-0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies. CONCLUSIONS: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.


Assuntos
Anemia/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Método Duplo-Cego , Feminino , Hemoglobinas/análise , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Diálise Renal , Equivalência Terapêutica , Resultado do Tratamento , Estados Unidos , Adulto Jovem
3.
Clin Nephrol ; 88(10): 190-197, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28766493

RESUMO

AIM: To assess the safety and immunogenicity of subcutaneous (SC) HX575 (epoetin-α) in dialysis- and nondialysis-dependent adult patients with chronic kidney disease (CKD). METHODS: Open-label, single-arm, multicenter study in patients (n = 416) from Germany, Italy, Poland, Romania, Russia, Turkey, and Ukraine. RESULTS: Mean (standard deviation (SD)) age was 52.3 (15.8) years, all patients were Caucasian, and similar proportions were male/female. 250 patients (60.1%) were erythropoiesis-stimulating agent (ESA)-naïve, and 166 (39.9%) were receiving ESA maintenance therapy at study start; mean (SD) on-study treatment duration with HX575 was 43.4 (15.8) weeks and 45.3 (13.7) weeks, respectively. Binding antierythropoietin (EPO) antibodies were detected by radioimmunoprecipitation (RIP) assay in 7 patients (1.7%; incidence 0.019); 5 of these were ESA-naïve at study entry. No patient developed neutralizing antibodies as determined in a cell-based epoetin neutralizing assay. Of the 7 patients with a positive binding anti-EPO RIP assay, 4 tested negative at later time points while continuing HX575 treatment. Three patients had low titers of anti-EPO antibodies at the last study assessment. There were no clinical signs of immunogenicity or hypersensitivity. CONCLUSIONS: SC HX575 was effective for correcting and maintaining correction of anemia, and the mean weekly dose remained stable over time.
.


Assuntos
Anemia/tratamento farmacológico , Epoetina alfa/efeitos adversos , Hematínicos/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Anemia/etiologia , Epoetina alfa/uso terapêutico , Eritropoetina , Europa (Continente) , Feminino , Hematínicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal Crônica/terapia
4.
Oncologist ; 21(7): 789-94, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27091420

RESUMO

BACKGROUND: Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy. METHODS: A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 × 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin. RESULTS: Baseline characteristics were well balanced. DSN was equivalent between groups at mean ± SD 1.36 ± 1.13 (LA-EP2006, n = 155) and 1.19 ± 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected. CONCLUSION: LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC. IMPLICATIONS FOR PRACTICE: The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.


Assuntos
Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Terapia Neoadjuvante , Neutropenia/prevenção & controle , Adulto , Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/patologia , Método Duplo-Cego , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polietilenoglicóis , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
5.
Curr Med Res Opin ; 38(6): 999-1009, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35392751

RESUMO

OBJECTIVE: The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States. METHODS: Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). In vitro biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer. RESULTS: No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation in vitro confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic. CONCLUSIONS: The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.


Assuntos
Medicamentos Biossimilares , Adulto , Medicamentos Biossimilares/efeitos adversos , Filgrastim/uso terapêutico , Humanos , Polietilenoglicóis/uso terapêutico , Equivalência Terapêutica , Estados Unidos
6.
AAPS J ; 22(1): 7, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792633

RESUMO

For biosimilar drug development programs, it is essential to demonstrate that there are no clinically significant differences between the proposed biosimilar therapeutic (biosimilar) and its reference product (originator). Based on a stepwise comprehensive comparability exercise, the biosimilar must demonstrate similarity to the originator in physicochemical characteristics, biological activity, pharmacokinetics, efficacy, and safety, including immunogenicity. The goal of the immunogenicity assessment is to evaluate potential differences between the proposed biosimilar product and the originator product in the incidence and severity of human immune responses. Establishing that there are no clinically meaningful differences in the immune response between the products is a key element in the demonstration of biosimilarity. An issue of practical, regulatory, and financial importance is to establish whether a two-assay (based on the biosimilar and originator respectively) or a one-assay approach (based on the biosimilar) is optimal for the comparative immunogenicity assessment. This paper recommends the use of a single, biosimilar-based assay for assessing immunogenic similarity in support of biosimilar drug development. The development and validation of an ADA assay used for a biosimilar program should include all the assessments recommended for an innovator program (10-16, 29). In addition, specific parameters also need to be evaluated, to gain confidence that the assay can detect antibodies against both the biosimilar and the originator. Specifically, the biosimilar and the originator should be compared in antigenic equivalence, to assess the ability of the biosimilar and the originator to bind in a similar manner to the positive control(s), as well as in the confirmatory assay and drug tolerance experiments. Practical guidance for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity of a biosimilar in comparison to the originator, using the one-assay approach, are described herein.


Assuntos
Medicamentos Biossimilares , Técnicas Imunológicas , Estudos de Validação como Assunto
7.
J Neurochem ; 107(2): 418-31, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18702663

RESUMO

Repulsive guidance molecule A (RGM A) was recently described as a potent inhibitor of neuroregeneration in a rat spinal cord injury model. The receptor mediating RGM A's repulsive activity was shown to be Neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of netrin receptors. Binding of RGM A to Neogenin induces activation of the small GTPase RhoA and of its effector Rho-kinase by an unknown mechanism. Here we show, that the cytoplasmic tail of Neogenin interacts directly with the transcriptional coactivator LIM domain only 4 (LMO4) in human SH-SY5Y cells, human Ntera neurons, and in embryonic rat cortical neurons. RGM A binding to Neogenin but not binding of Netrin-1, induces release of LMO4 from Neogenin. Down-regulation of LMO4 neutralizes the repulsive activity of RGM A in neuronal cell lines and embryonic rat cortical neurons and prevents RhoA activation. These results show for the first time that an interaction of Neogenin with LMO4 is involved in the RGM A - Neogenin signal transduction pathway for RhoA activation.


Assuntos
Proteínas de Homeodomínio/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Amidas/farmacologia , Análise de Variância , Animais , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Proteínas Ligadas por GPI , Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Homeodomínio/biossíntese , Humanos , Proteínas com Domínio LIM , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Estrutura Terciária de Proteína , Piridinas/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Fatores de Transcrição/biossíntese , Transfecção/métodos , Tubulina (Proteína)/farmacologia , Técnicas do Sistema de Duplo-Híbrido , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Philos Trans R Soc Lond B Biol Sci ; 361(1473): 1513-29, 2006 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-16939972

RESUMO

During the development of the nervous system, outgrowing axons often have to travel long distances to reach their target neurons. In this process, outgrowing neurites tipped with motile growth cones rely on guidance cues present in their local environment. These cues are detected by specific receptors expressed on growth cones and neurites and influence the trajectory of the growing fibres. Neurite growth, guidance, target innervation and synapse formation and maturation are the processes that occur predominantly but not exclusively during embryonic or early post-natal development in vertebrates. As a result, a functional neural network is established, which is usually remarkably stable. However, the stability of the neural network in higher vertebrates comes at an expensive price, i.e. the loss of any significant ability to regenerate injured or damaged neuronal connections in their central nervous system (CNS). Most importantly, neurite growth inhibitors prevent any regenerative growth of injured nerve fibres. Some of these inhibitors are associated with CNS myelin, others are found at the lesion site and in the scar tissue. Traumatic injuries in brain and spinal cord of mammals induce upregulation of embryonic inhibitory or repulsive guidance cues and their receptors on the neurites. An example for embryonic repulsive directional cues re-expressed at lesion sites in both the rat and human CNS is provided with repulsive guidance molecules, a new family of directional guidance cues.


Assuntos
Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Efrina-A5/metabolismo , Neurônios/citologia , Animais , Sistema Nervoso Central/metabolismo , Efrina-A5/química , Neurônios/metabolismo , Transdução de Sinais
9.
Mol Cell ; 23(6): 887-97, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16973440

RESUMO

Aberrant folding and fibrillar aggregation by polyglutamine (polyQ) expansion proteins are associated with cytotoxicity in Huntington's disease and other neurodegenerative disorders. Hsp70 chaperones have an inhibitory effect on fibril formation and can alleviate polyQ cytotoxicity. Here we show that the cytosolic chaperonin, TRiC, functions synergistically with Hsp70 in this process and is limiting in suppressing polyQ toxicity in a yeast model. In vitro reconstitution experiments revealed that TRiC, in cooperation with the Hsp70 system, promotes the assembly of polyQ-expanded fragments of huntingtin (Htt) into soluble oligomers of approximately 500 kDa. Similar oligomers were observed in yeast cells upon TRiC overexpression and were found to be benign, in contrast to conformationally distinct Htt oligomers of approximately 200 kDa, which accumulated at normal TRiC levels and correlated with inhibition of cell growth. We suggest that TRiC cooperates with the Hsp70 system as a key component in the cellular defense against amyloid-like protein misfolding.


Assuntos
Chaperoninas/fisiologia , Peptídeos/química , Chaperoninas/metabolismo , Expansão das Repetições de DNA , Proteínas de Fluorescência Verde/análise , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Peptídeos/metabolismo , Dobramento de Proteína , Proteínas Recombinantes de Fusão/análise , Sequências Repetitivas de Aminoácidos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
10.
Biochem Biophys Res Commun ; 333(4): 1202-10, 2005 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-15978545

RESUMO

Protein aggregation is the key event in a number of human diseases such as Alzheimer's and Parkinson's disease. We present a general method to quantify and characterize protein aggregates by dual-colour scanning for intensely fluorescent targets (SIFT). In addition to high sensitivity, this approach offers a unique opportunity to study co-aggregation processes. As the ratio of two fluorescently labelled components can be analysed for each aggregate separately in a homogeneous assay, the molecular composition of aggregates can be studied even in samples containing a mixture of different types of aggregates. Using this method, we could show that wild-type alpha-synuclein forms co-aggregates with a mutant variant found in familial Parkinson's disease. Moreover, we found a striking increase in aggregate formation at non-equimolar mixing ratios, which may have important therapeutic implications, as lowering the relative amount of aberrant protein may cause an increase of protein aggregation leading to adverse effects.


Assuntos
Amiloide/química , Amiloide/ultraestrutura , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/ultraestrutura , Espectrometria de Fluorescência/métodos , Amiloide/análise , Sítios de Ligação , Dimerização , Complexos Multiproteicos/análise , Complexos Multiproteicos/química , Complexos Multiproteicos/ultraestrutura , Proteínas do Tecido Nervoso/análise , Ligação Proteica , Sinucleínas , alfa-Sinucleína
11.
Semin Cell Dev Biol ; 15(1): 17-29, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15036203

RESUMO

Human misfolding diseases result from the failure of proteins to reach their active state or from the accumulation of aberrantly folded proteins. The mechanisms by which molecular chaperones influence the development of these diseases is beginning to be understood. Mutations that compromise the activity of chaperones lead to several rare syndromes. In contrast, the more frequent amyloid-related neurodegenerative diseases are caused by a gain of toxic function of misfolded proteins. Toxicity in these disorders may result from an imbalance between normal chaperone capacity and production of dangerous protein species. Increased chaperone expression can suppress the neurotoxicity of these molecules, suggesting possible therapeutic strategies.


Assuntos
Doença/etiologia , Chaperonas Moleculares/fisiologia , Dobramento de Proteína , Proteínas/química , Amiloide/química , Amiloide/fisiologia , Chaperonina 60/genética , Chaperonina 60/fisiologia , Chaperoninas/fisiologia , Cisteína Endopeptidases/fisiologia , Citosol/fisiologia , Retículo Endoplasmático/fisiologia , Proteínas do Olho/genética , Proteínas do Olho/fisiologia , Proteínas de Ligação ao GTP , Chaperoninas do Grupo II , Proteínas de Choque Térmico HSP70/fisiologia , Proteínas de Choque Térmico HSP90/fisiologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Modelos Biológicos , Chaperonas Moleculares/genética , Complexos Multienzimáticos/fisiologia , Mutação , Complexo de Endopeptidases do Proteassoma , Proteínas/fisiologia , Ubiquitinas/fisiologia , alfa-Cristalinas/genética , alfa-Cristalinas/fisiologia
12.
Mol Cell ; 15(1): 95-105, 2004 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225551

RESUMO

The expression of polyglutamine-expanded mutant proteins in Huntington's disease and other neurodegenerative disorders is associated with the formation of intraneural inclusions. These aggregates could potentially cause cellular toxicity by sequestering essential proteins possessing normal polyQ repeats, including the transcription factors TBP and CBP. We show, in vitro and in cells, that monomers or small soluble oligomers of huntingtin exon1 accumulate in the nucleus and inhibit the function of TBP in a polyQ-dependent manner. FRET experiments indicate that these toxic forms are generated through a conformational rearrangement in huntingtin. Interaction of toxic huntingtin with the benign polyQ repeat of TBP structurally destabilizes the transcription factor, independent of the formation of insoluble coaggregates. Hsp70/Hsp40 chaperones interfere with the conformational change in mutant huntingtin and inhibit the deactivation of TBP. These results outline a molecular mechanism of cellular toxicity in polyQ disease and can explain the beneficial effects of molecular chaperones.


Assuntos
Proteínas do Tecido Nervoso/toxicidade , Proteínas Nucleares/toxicidade , Peptídeos/genética , Fatores de Transcrição/antagonistas & inibidores , Expansão das Repetições de Trinucleotídeos/genética , Animais , Proteína de Ligação a CREB , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Éxons , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteína Huntingtina , Substâncias Macromoleculares , Camundongos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Peptídeos/metabolismo , Conformação Proteica , Dobramento de Proteína , Saccharomyces cerevisiae , Proteína de Ligação a TATA-Box/antagonistas & inibidores , Proteína de Ligação a TATA-Box/genética , Proteína de Ligação a TATA-Box/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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