RESUMO
Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their functional interaction with different viruses. Whether E3 ubiquitin ligases help in the elimination of viral components or viruses utilize their molecular capabilities in their intracellular propagation is not clear. The first time our current article comprehends fundamental concepts and new insights on the different viruses and their interaction with various E3 Ubiquitin Ligases. In this review, we highlight the molecular pathomechanism of viruses linked with E3 Ubiquitin Ligases dependent mechanisms. An enhanced understanding of E3 Ubiquitin Ligase-mediated removal of viral proteins may open new therapeutic strategies against viral infections.
Assuntos
Ubiquitina-Proteína Ligases/fisiologia , Proteínas Virais/fisiologia , Viroses/enzimologia , Replicação Viral/fisiologia , Transformação Celular Viral/fisiologia , Proteínas Culina/fisiologia , Endossomos/virologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/enzimologia , Inflamação/virologia , Neoplasias/enzimologia , Neoplasias/virologia , Vírus Oncogênicos/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas com Motivo Tripartido/fisiologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Viroses/imunologia , Viroses/virologia , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Intracellular/extracellular protein aggregation is linked to a variety of neurodegenerative diseases. Current research focuses on identifying antiamyloidogenic small molecules to inhibit such protein aggregation and associated cytotoxicity. We have recently demonstrated that transforming these antiamyloidogenic small molecules into nanoparticle forms can greatly improve their performance, and biocompatible/biodegradable formulation of such nanoparticles is critical for therapeutic applications. Here, we report polylactide (PL)-based biodegradable nanoparticles for improved neuroprotection against polyglutamine (polyQ) aggregation that is responsible for Huntington's disease. PL is terminated with an antiamyloidogenic trehalose molecule or the neurotransmitter dopamine, and the resultant nanoparticle is loaded with the antiamyloidogenic catechin molecule. The self-assembled nanoparticle is â¼200 nm in size and enters into the neuronal cell, inhibits polyQ aggregation, lowers oxidative stress, and enhances cell proliferation against polyQ aggregates. This biodegradable polymer can be used in nanoformulation of other reported antiamyloidogenic molecules for testing various animal models of neurodegenerative diseases.
Assuntos
Catequina , Nanopartículas , Animais , Catequina/farmacologia , Neuroproteção , Peptídeos , Poliésteres , Trealose/farmacologiaRESUMO
Amyloid protein aggregation is responsible for a variety of neurodegenerative diseases, and antiamyloidogenic small molecules are identified for inhibiting such protein aggregation at extra-/intracellular space. We show that the nanoparticle form of small molecules offers better antiamyloidogenic performance via enhanced bioavailability and multivalent binding with protein. Here, we report hyperbranched polyglycerol dendrimers terminated with antiamyloidogenic small molecules such as gallate, tyrosine, and trehalose and their potential in inhibiting lysozyme/huntingtin protein aggregation under intra-/extracellular space. The synthesized functional dendrimers are â¼5 nm in size having an average molecular weight of â¼2000 Da, and they are highly biocompatible in nature. We found that functional dendrimers are efficient in micromolar doses with respect to molecular forms that are effective at millimolar concentration. It is observed that the trehalose-terminated dendrimer is more effective in inhibiting protein aggregation, whereas the gallate-terminated dendrimer is more effective in disintegrating mature protein fibrils. This approach can be used to design functional dendrimers as potential nanodrugs for the treatment of various neurodegenerative diseases.
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Dendrímeros , Glicerol , Polímeros , Agregados ProteicosRESUMO
Protein aggregation is linked to variety of neurodegenerative disorders and other diseases. Current research involves understanding the mechanism of protein aggregation, inhibiting protein aggregation under intra/extracellular space, lowering toxicity arising due to soluble oligomers, and augmenting the clearance of protein aggregates from the brain. Toward this direction, different types of antiamyloidogenic small molecules, macromolecules, and nanomaterials are identified that can inhibit protein aggregation, and extensive progress has been made for their effective utilization. Here, we summarize our effort in designing a nanoparticle form of antiamyloidogenic molecules with enhanced performance under in vitro and in vivo conditions. We found that the nanoparticle form of antiamyloidogenic molecules can perform up to 100,000-times better than the respective molecular form due to the combined effect of enhanced bioavailability at intra/extracellular space and multivalent binding property with aggregating protein. This work demonstrates that further research should be directed toward designing nanoparticle forms of antiamyloidogenic molecules for their effective performance.
Assuntos
Encéfalo/efeitos dos fármacos , Nanopartículas/química , Doenças Neurodegenerativas/tratamento farmacológico , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Amiloide/antagonistas & inibidores , Encéfalo/metabolismo , Humanos , Nanopartículas/administração & dosagemRESUMO
Trehalose is a well-known antiamyloidogenic molecule that inhibits protein aggregation under the intracellular/extracellular condition, and recent work shows that the nanoparticle form of trehalose can further enhance this performance. Here we have designed a trehalose-functionalized Au nanoparticle that can inhibit the aggregation of a polyglutamine-containing mutant protein inside the neuronal cell. Designed nanoparticles have a 20-30 nm Au core with about 350 ± 50 trehalose molecules per particle on the surface on average. They enter the cell, inhibit mutant protein aggregation, and enhance the cell survival against toxic protein aggregates. This work extends the application potential of trehalose for the understanding and treatment of different diseases involving protein aggregation.
Assuntos
Trealose/química , Sobrevivência Celular , Citoplasma , Ouro , Espaço Intracelular , Nanopartículas MetálicasRESUMO
Angelman syndrome and autism are neurodevelopmental disorders linked to mutations and duplications of an E3 ligase called ube3a respectively. Since cognitive deficits and learning disabilities are hallmark symptoms of both these disorders, we investigated a role for dube3a in the learning ability of flies using the aversive phototaxis suppression assay. We show that down and up-regulation of dube3a are both detrimental to learning in larvae and adults. Using conditional gene expression we found that dube3a is required for normal brain development and during adulthood. Furthermore, we suggest that dube3a could be interacting with other learning and memory genes such as derailed. Along with firmly establishing dube3a as a gene that is required for learning, our work also opens avenues for further understanding the role played by this gene in brain development and behavior.
Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Aprendizagem , Ubiquitina-Proteína Ligases/genética , Animais , Animais Geneticamente Modificados , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Immunoblotting , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Memória , Atividade Motora/genética , Corpos Pedunculados/metabolismo , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Inhibition of amyloid fibrillation and clearance of amyloid fibrils/plaques are essential for the prevention and treatment of various neurodegenerative disorders involving protein aggregation. Herein, we report curcumin-functionalized gold nanoparticles (Au-curcumin) of hydrodynamic diameter 10-25â nm, which serve to inhibit amyloid fibrillation and disintegrate/dissolve amyloid fibrils. In nanoparticle form, curcumin is water-soluble and can efficiently interact with amyloid protein/peptide, offering enhanced performance in inhibiting amyloid fibrillation and dissolving amyloid fibrils. Our results imply that nanoparticle-based artificial molecular chaperones may offer a promising therapeutic approach to combat neurodegenerative disease.
Assuntos
Amiloide/antagonistas & inibidores , Amiloide/ultraestrutura , Curcumina/farmacologia , Ouro/farmacologia , Nanopartículas/química , Sequência de Aminoácidos , Amiloide/química , Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Curcumina/química , Ouro/química , Humanos , Dados de Sequência Molecular , Nanopartículas/ultraestrutura , Solubilidade/efeitos dos fármacosRESUMO
Direct cytosolic delivery of large biomolecules that bypass the endocytic pathways is a promising strategy for therapeutic applications. Recent works have shown that small-molecule, nanoparticle, and polymer-based carriers can be designed for direct cytosolic delivery. It has been shown that the specific surface chemistry of the carrier, nanoscale assembly between the carrier and cargo molecule, good colloidal stability, and low surface charge of the nano-assembly are critical for non-endocytic uptake processes. Here we report a guanidinium-terminated polyaspartic acid micelle for direct cytosolic delivery of protein and DNA. The polymer delivers the protein/DNA directly to the cytosol by forming a nano-assembly, and it is observed that <200 nm size of colloidal assembly with near-zero surface charge is critical for efficient cytosolic delivery. This work shows the importance of size and colloidal property of the nano-assembly for carrier-based cytosolic delivery of large biomolecules.
Assuntos
Materiais Biocompatíveis/química , Citosol/química , DNA/genética , Nanopartículas Metálicas/química , Peptídeos/química , Soroalbumina Bovina/química , Animais , Bovinos , Coloides/química , DNA/química , Guanidina/química , Humanos , Células KB , Teste de Materiais , Micelas , Estrutura Molecular , Tamanho da PartículaRESUMO
Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.
Assuntos
Doença de Huntington/tratamento farmacológico , Doença de Huntington/patologia , Peptídeos/metabolismo , Trealose/uso terapêutico , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Glucose/administração & dosagem , Glucose/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Mioglobina/genética , Mioglobina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMO
Autophagy is a cellular self-clearance process for maintaining regular cytoplasmic function, and modulation of autophagy can influence cytotoxicity, apoptosis, and clearance of toxic amyloid fibril. In a recent work, functional nanoparticles are used to modulate autophagy. However, the role of nanoparticle uptake mechanisms and their intracellular processing on autophagy is vaguely understood. Here, we show that autophagy is influenced by nanoparticle surface chemistry-directed intracellular trafficking and localization. In particular, we have designed iron oxide nanoparticles functionalized with arginine/arginine methyl ester/octyl/oleyl/cholesterol with a high cell uptake property. We found that autophagy is induced by octyl/oleyl functionalization without appreciable cell death. Further study shows that enhanced cytosolic delivery over membrane localization and increased intracellular aggregation over homogeneous cytosolic distribution lead to autophagy induction via intracellular reactive oxygen species generation. The observed result can be used to design functional nanoparticles/nanodrugs for modulating cellular autophagy that can be used in various biomedical applications.
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Quercetin is a dietary flavonoid that shows effective neuroprotective action in cellular and animal models of Alzheimer's disease and Huntington's disease. However, its therapeutic application is limited due to low water solubility and cytotoxicity at the working concentration in the 20-100 µM range. Here we report a nanoparticle form of quercetin (nanoquercetin) that shows antiamyloidogenic performance at lower quercetin concentration (one micromolar) and inhibits polyglutamine (mutant huntingtin) aggregation in Huntington's disease cell model. Nanoquercetin is composed of a polyaspartic acid-based polymer micelle encapsulated with quercetin (3-5 wt %) and colloidal in nature with <100 nm hydrodynamic size. It enters into the cell via endocytosis and slowly releases molecular quercetin in a >3 day time scale that offers better antiamyloidogenic performance via up-regulated autophagy processes. This work shows that nanoformulation of antiamyloidogenic molecule can have better performance as compared to respective molecule.
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Inhibiting protein aggregation under intra-/extracellular space and clearing protein aggregates from the brain are two critical issues for the treatment of various neurodegenerative diseases. Although a variety of anti-amyloidogenic chemicals/biochemicals have been identified for inhibiting such protein aggregation, clearing protein aggregates is a challenging issue. Here we report a designed biopolymer micelle of 15-30 nm hydrodynamic size that can clear protein aggregates from cells via an up-regulated autophagy process. The polymer has a polyaspartic acid backbone and is functionalized with fatty amine, arginine, and primary amine for inducing self-assembly, enhancing cell uptake, and up-regulating autophagy processes, respectively. The polymer micelle (PM) enters into the cell via lipid raft endocytosis, is transported to the perinuclear region where the protein oligomer/aggregate predominantly localizes, clears aggregated protein from the cell, and enhances the cell's survival against toxic protein aggregates. The designed PM may be used as a drug delivery carrier for anti-amyloidogenic drugs for enhanced efficacy in the treatment of neurodegenerative diseases.
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Sugar-based osmolyte molecules are known to stabilize proteins under stress, but usually they have poor chaperone performance in inhibiting protein aggregation. Here, we show that the nanoparticle form of sugars molecule can enhance their chaperone performance typically by 102-105 times, compared to molecular sugar. Sugar-based plate-like nanoparticles of 20-40 nm hydrodynamic size have been synthesized by simple heating of acidic aqueous solution of glucose/sucrose/maltose/trehalose. These nanoparticles have excitation-dependent green/yellow/orange emission and surface chemistry identical to the respective sugar molecule. Fibrillation of lysozyme/insulin/amyloid beta in extracellular space, aggregation of mutant huntingtin protein inside model neuronal cell, and cytotoxic effect of fibrils are investigated in the presence of these sugar nanoparticles. We found that sugar nanoparticles are 102-105 times efficient than respective sugar molecules in inhibiting protein fibrillation and preventing cytotoxicity arising of fibrils. We propose that better performance of the nanoparticle form is linked to its stronger binding with fibril structure and enhanced cell uptake. This result suggests that nanoparticle form of osmolyte can be an attractive option in prevention and curing of protein aggregation-derived diseases.
Assuntos
Nanopartículas , Amiloide , Peptídeos beta-Amiloides , Chaperonas Moleculares , AçúcaresRESUMO
Prevention and therapeutic strategies for various neurodegenerative diseases focus on inhibiting protein fibrillation, clearing aggregated protein plaques from the brain, and lowering protein-aggregate-induced toxicity. We have designed poly(trehalose) nanoparticles that can inhibit amyloid/polyglutamine aggregation under extra-/intracellular conditions, reduce such aggregation-derived cytotoxicity, and prevent polyglutamine aggregation in a Huntington's disease (HD) model mouse brain. The nanoparticles have a hydrodynamic size of 20-30 nm and are composed of a 6 nm iron oxide core and a zwitterionic polymer shell containing â¼5-12 wt % covalently linked trehalose. The designed poly(trehalose) nanoparticles are 1000-10000 times more efficient than molecular trehalose in inhibiting protein fibrillation in extra-cellular space, in blocking aggregation of polyglutamine-containing mutant huntingtin protein in model neuronal cells, and in suppressing mutant huntingtin aggregates in HD mouse brain. We show that the nanoparticle form of trehalose with zwitterionic surface charge and a trehalose multivalency (i.e., number of trehalose molecules per nanoparticle) of â¼80-200 are crucial for efficient brain targeting, entry into neuronal cells, and suppression of mutant huntingtin aggregation. The present work shows that nanoscale trehalose can offer highly efficient antiamyloidogenic performance at micromolar concentration, compared with millimollar to molar concentrations for molecular trehalose. This approach can be extended to in vivo application to combat protein-aggregation-derived neurodegenerative diseases.
Assuntos
Nanopartículas , Animais , Doença de Huntington , Camundongos , Proteínas do Tecido Nervoso , Peptídeos , TrealoseRESUMO
Green tea polyphenol epigallocatechin-3-gallate (EGCG) is known for its antiamyloidogenic property, and it is observed that molecular EGCG binds with amyloid structure, redirects fibrillation kinetics, remodels mature fibril, and lowers the amyloid-derived toxicity. However, this unique property of EGCG is difficult to utilize because of their poor chemical stability and substandard bioavailability. Here we report a nanoparticle form of EGCG of 25 nm size (nano-EGCG) which is 10-100 times more efficient than molecular EGCG in inhibiting protein aggregation, disintegrating mature protein aggregates, and lowering amyloidogenic cytotoxicity. The most attractive advantage of nano-EGCG is that it efficiently protects neuronal cells from the toxic effect of extracellular amyloid beta or intracellular mutant huntingtin protein aggregates by preventing their aggregation. We found that the better performance of nano-EGCG is due to the combined effect of increased chemical stability of EGCG against degradation, stronger binding with protein aggregates, and efficient entry into the cell for interaction with aggregated protein structure. This result indicates that the nanoparticle form of antiamyloidogenic molecules can be more powerful in prevention and curing of protein aggregation derived diseases.
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Aggregation of proteins with the expansion of polyglutamine tracts in the brain underlies progressive genetic neurodegenerative diseases (NDs) like Huntington's disease and spinocerebellar ataxias (SCA). An insensitive cellular proteotoxic stress response to non-native protein oligomers is common in such conditions. Indeed, upregulation of heat shock factor 1 (HSF1) function and its target protein chaperone expression has shown promising results in animal models of NDs. Using an HSF1 sensitive cell based reporter screening, we have isolated azadiradione (AZD) from the methanolic extract of seeds of Azadirachta indica, a plant known for its multifarious medicinal properties. We show that AZD ameliorates toxicity due to protein aggregation in cell and fly models of polyglutamine expansion diseases to a great extent. All these effects are correlated with activation of HSF1 function and expression of its target protein chaperone genes. Notably, HSF1 activation by AZD is independent of cellular HSP90 or proteasome function. Furthermore, we show that AZD directly interacts with purified human HSF1 with high specificity, and facilitates binding of HSF1 to its recognition sequence with higher affinity. These unique findings qualify AZD as an ideal lead molecule for consideration for drug development against NDs that affect millions worldwide.
Assuntos
DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Limoninas/farmacologia , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Peptídeos/metabolismo , Extratos Vegetais/farmacologia , Agregação Patológica de Proteínas , Animais , Azadirachta/química , DNA/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células HCT116 , Células HEK293 , Fatores de Transcrição de Choque Térmico/genética , Humanos , Limoninas/isolamento & purificação , Limoninas/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Ligação Proteica , Sementes , Fatores de Tempo , TransfecçãoRESUMO
Growth factor receptor protein binding protein 2 (Grb2) is known to be associated with intracellular growth and proliferation related signaling cascades. Huntingtin (Htt), a ubiquitously expressed protein, when mutated, forms toxic intracellular aggregates - the hallmark of Huntington's disease (HD). We observed an elevated expression of Grb2 in neuronal cells in animal and cell models of HD. Grb2 overexpression was predominantly regulated by the transcription factor Forkhead Box D3 (Foxd3). Exogenous expression of Grb2 also reduced aggregation of mutant Htt in Neuro2A cells. Grb2 is also known to interact with Htt, depending on epidermal growth factor receptor (EGFR) activation. Grb2- mutant Htt interaction in the contrary, took place in vesicular structures, independent of EGFR activation that eventually merged with autophagosomes and activated the autophagy machinery helping in autophagosome and lysosome fusion. Grb2, with its emerging dual role, holds promise for a survival mechanism for HD.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Proteína Adaptadora GRB2/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/metabolismo , Animais , Autofagia/genética , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Proteína Adaptadora GRB2/genética , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Microscopia Confocal , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fagossomos/metabolismo , Ligação Proteica , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transcrição Gênica , Regulação para CimaRESUMO
Huntington's disease (HD) is caused by the expansion of N-terminal polymorphic poly Q stretch of the protein huntingtin (HTT). Deregulated microRNAs and loss of function of transcription factors recruited to mutant HTT aggregates could cause characteristic transcriptional deregulation associated with HD. We observed earlier that expressions of miR-125b, miR-146a and miR-150 are decreased in STHdh(Q111)/Hdh(Q111) cells, a model for HD in comparison to those of wild type STHdh(Q7)/Hdh(Q7) cells. In the present manuscript, we show by luciferase reporter assays and real time PCR that decreased miR-146a expression in STHdh(Q111)/Hdh(Q111) cells is due to decreased expression and activity of p65 subunit of NFkB (RelA/NFkB). By reporter luciferase assay, RT-PCR and western blot analysis, we also show that both miR-150 and miR-125b target p53. This partially explains the up regulation of p53 observed in HD. Elevated p53 interacts with RelA/NFkB, reduces its expression and activity and decreases the expression of miR-146a, while knocking down p53 increases RelA/NFkB and miR-146a expressions. We also demonstrate that expression of p53 is increased and levels of RelA/NFkB, miR-146a, miR-150 and miR-125b are decreased in striatum of R6/2 mice, a mouse model of HD and in cell models of HD. In a cell model, this effect could be reversed by exogenous expression of chaperone like proteins HYPK and Hsp70. We conclude that (i) miR-125b and miR-150 target p53, which in turn regulates RelA/NFkB and miR-146a expressions; (ii) reduced miR-125b and miR-150 expressions, increased p53 level and decreased RelA/NFkB and miR-146a expressions originate from mutant HTT (iii) p53 directly or indirectly regulates the expression of miR-146a. Our observation of interplay between transcription factors and miRNAs using HD cell model provides an important platform upon which further work is to be done to establish if such regulation plays any role in HD pathogenesis.