RESUMEN
Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/fisiología , Neuronas/fisiología , Proteínas Nucleares/fisiología , Proteínas Represoras/genética , Factores de Transcripción/genética , Animales , Línea Celular , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Ratas , Ratas Sprague-Dawley , Proteínas Represoras/fisiología , Elementos Silenciadores Transcripcionales , Factores de Transcripción/fisiología , Transcripción GenéticaRESUMEN
Technetium-99m is the workhorse of diagnostic nuclear medicine. The aim of the work is to analyze the technetium-99m patents since 2000 to photograph its innovation. QUESTEL's ORBIT Intelligence system was used for the collection of technetium inventions disclosed in patents and patent applications in more than 96 countries in the period 2000-2022; 2768 patent documents were analyzed. Patent counting and analysis have shown that SPECT imaging using technetium-99m radiopharmaceuticals is still robust. The introduction of new technetium-99m radiopharmaceuticals into clinical routine goes beyond successful trials. In eastern economies, such as China and other emerging markets, patent applications are on the rise, while those in developed western countries are stagnating, with some exceptions for the United States. But despite the difficulties, academic and industrial research on these tracers remains essential for the development of nuclear medicine.
Asunto(s)
Radiofármacos , Tecnecio , Estados Unidos , Tomografía Computarizada de Emisión de Fotón Único , ChinaRESUMEN
BACKGROUND: There is an urgent need of neuronal cell models to be applied to high-throughput screening settings while recapitulating physiological and/or pathological events occurring in the Central Nervous System (CNS). Stem cells offer a great opportunity in this direction since their self renewal capacity allows for large scale expansion. Protocols for directed differentiation also promise to generate populations of biochemically homogenous neuronal progenies. NS (Neural Stem) cells are a novel population of stem cells that undergo symmetric cell division in monolayer and chemically defined media, while remaining highly neurogenic. RESULTS: We report the full adaptation of the NS cell systems for their growth and neuronal differentiation to 96- and 384-well microplates. This optimized system has also been exploited in homogeneous and high-content assays. CONCLUSIONS: Our results show that these mouse NS cells may be suitable for a series of applications in high-throughput format.
Asunto(s)
Células Madre Adultas/fisiología , Técnicas de Cultivo de Célula/instrumentación , Técnicas de Cultivo de Célula/métodos , Ensayos Analíticos de Alto Rendimiento/instrumentación , Ensayos Analíticos de Alto Rendimiento/métodos , Neuronas/fisiología , Animales , Apoptosis , Diferenciación Celular , Línea Celular , Supervivencia Celular , AMP Cíclico/metabolismo , Ratones , Ratones Endogámicos , Neurogénesis , Estrés Oxidativo/fisiología , Receptores de GABA-A/metabolismo , Nicho de Células Madre/fisiología , Factores de TiempoRESUMEN
Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Carmustina/farmacología , Dacarbazina/análogos & derivados , Glioma/ultraestructura , Heterocromatina/efectos de los fármacos , Acetilación/efectos de los fármacos , Apoptosis , Línea Celular Tumoral , Senescencia Celular , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/metabolismo , Metilación de ADN/efectos de los fármacos , Dacarbazina/farmacología , Heterocromatina/metabolismo , Heterocromatina/ultraestructura , Histonas/metabolismo , Humanos , Proteína 2 de Unión a Metil-CpG/metabolismo , TemozolomidaRESUMEN
REST/NRSF is a multifunctional transcription factor that represses or silences many neuron-specific genes in both neural and non-neural cells by recruitment to its cognate RE1/NRSE regulatory sites. An increase in RE1/NRSE genomic binding is found in Huntington's disease (HD), resulting in the repression of REST/NRSF regulated gene transcription, among which BDNF, thus representing one of the possible detrimental effectors in HD. Three 2-aminothiazole derivatives were recently identified as potent modulators of the RE1/NRSE silencing activity through a cell-based gene reporter assay. In this study, the structure-activity relationships (SAR) of a library of commercially available 2-aminoisothiazoles diversely substituted at the amino group or at position 4 has been evaluated. A quantitative structure-activity relationship analysis performed using the Phase strategy yielded highly predictive 3D-QSAR pharmacophore model for in silico drug screening.
Asunto(s)
Enfermedad de Huntington/genética , Tiazoles/química , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Biblioteca de Genes , Silenciador del Gen/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Proteínas Represoras/efectos de los fármacos , Proteínas Represoras/genética , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacología , Tiazoles/uso terapéutico , Transcripción Genética/efectos de los fármacosRESUMEN
CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death.
Asunto(s)
Proteínas Portadoras/metabolismo , Caspasa 1/metabolismo , Caspasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Secuencia de Aminoácidos , Animales , Células COS , Proteínas Portadoras/química , Caspasa 1/química , Caspasas/química , Caspasas Iniciadoras , Muerte Celular , Células Cultivadas , Chlorocebus aethiops , Retículo Endoplásmico/metabolismo , Activación Enzimática , Células HeLa , Humanos , Interleucina-1/metabolismo , Ratones , Mitocondrias/metabolismo , Modelos Biológicos , Datos de Secuencia Molecular , Interferencia de ARN , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con ReceptoresRESUMEN
The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an approximately 50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dose-dependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.
Asunto(s)
Colesterol/biosíntesis , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Neuronas/fisiología , Análisis de Varianza , Animales , Western Blotting/métodos , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Células Cultivadas , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inmunohistoquímica/métodos , Ratones , Neuronas/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Transporte de Proteínas/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Tiempo , Transfección/métodosRESUMEN
BACKGROUND: JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a approximately 1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3Deltaex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. RESULTS: To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Deltaex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. CONCLUSIONS: These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival.
Asunto(s)
Línea Celular , Cerebelo/citología , Glicoproteínas de Membrana/genética , Mitocondrias/ultraestructura , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Chaperonas Moleculares/genética , Lipofuscinosis Ceroideas Neuronales/genética , Animales , Transporte Biológico , Catepsina D/metabolismo , Cerebelo/metabolismo , Cerebelo/ultraestructura , Modelos Animales de Enfermedad , Endocitosis , Homocigoto , Lisosomas/ultraestructura , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Mutantes , Chaperonas Moleculares/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Neuronas/citología , Neuronas/metabolismo , Células Madre/metabolismo , Células Madre/ultraestructuraAsunto(s)
Enfermedad de Huntington/genética , Animales , Encéfalo/patología , Química Encefálica , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/fisiología , Cromosomas Humanos Par 4 , Factor Neurotrófico Ciliar/fisiología , Glutamina/genética , Humanos , Proteína Huntingtina , Enfermedad de Huntington/patología , Enfermedad de Huntington/terapia , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Péptidos/análisis , Péptidos/genética , Péptidos/metabolismo , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
REST/NRSF is a transcription factor that represses transcription of several neuronal genes by binding to a DNA regulatory motif known as Repressor Element 1/Neuron-restrictive silencer element (RE1/NRSE). In Huntington's Disease, an inherited degenerative disease affecting the brain, REST/NRSF enters pathologically into the nucleus of affected cells, leading to the activation of the RE1/NRSE sites and causing decreased transcription of several important neuronal genes. Following this discovery, an effort has begun by some of the authors aimed at identifying compounds capable of antagonizing REST/NRSF silencing activity. Here we will review the underlying basis for focusing pharmaceutical efforts on REST/NRSF-RE1/NRSE system as well as some of the strategies for a rational drug design approach. We will highlight approaches aimed at identifying or designing small molecules able to impact REST/NRSF nuclear translocation, its DNA binding or, more generally, the formation of the REST/NRSF transcriptional complex, in the attempt to restore neuronal gene transcription in pathological conditions of the brain.
Asunto(s)
Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Represoras/metabolismo , Terapia Genética , Humanos , Proteínas Represoras/genéticaRESUMEN
Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.
Asunto(s)
Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica , Silenciador del Gen , Proteína Huntingtina , Inmunohistoquímica , Luciferasas/metabolismo , Modelos Químicos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Péptidos/química , Ratas , Factores de Transcripción/metabolismoRESUMEN
Treatment of neurodegenerative diseases represents a major challenge for the pharmaceutical industry. Key to developing novel and efficacious therapeutics is the discovery of new druggable targets. Toward this aim, the current drug discovery process is strongly relying on the improved understanding of disease mechanisms and on a synergistic approach with chemistry, molecular biology and robotics. In this scenario, we present the case of a newly discovered molecular mechanism that may be of interest for drug discovery programmes in Huntington's disease and other neurodegenerative diseases.
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Diseño de Fármacos , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neurodegenerativas/etiología , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Proteína Huntingtina , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Huntington's Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterized by the presence of aggregates, transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli, increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptotic factors, are aberrantly released from brain-derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are also found in post-mortem HD brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington's Disease.
Asunto(s)
Proteínas Portadoras/metabolismo , Enfermedad de Huntington/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Encéfalo/metabolismo , Línea Celular , Supervivencia Celular , Ciclosporina/farmacología , Citosol/metabolismo , Serina Peptidasa A2 que Requiere Temperaturas Altas , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Proteínas Inhibidoras de la Apoptosis , Péptidos y Proteínas de Señalización Intracelular , Ratones , Mitocondrias/metabolismo , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pirimidinonas/farmacología , Tionas/farmacología , Ubiquitina-Proteína Ligasas , Proteína Inhibidora de la Apoptosis Ligada a XRESUMEN
Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Empalme Alternativo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Expresión Génica , Enfermedad de Huntington/genética , Ratones , Ratones Transgénicos , ARN Mensajero/análisis , ARN Mensajero/metabolismoRESUMEN
Huntington's disease (HD) is caused by a polyglutamine expansion in the amino-terminal region of huntingtin. Mutant huntingtin is proteolytically cleaved by caspases, generating amino-terminal aggregates that are toxic for cells. The addition of calpains to total brain homogenates also leads to cleavage of wild-type huntingtin, indicating that proteolysis of mutant and wild-type huntingtin may play a role in HD. Here we report that endogenous wild-type huntingtin is promptly cleaved by calpains in primary neurons. Exposure of primary neurons to glutamate or 3-nitropropionic acid increases intracellular calcium concentration, leading to loss of intact full-length wild-type huntingtin. This cleavage could be prevented by calcium chelators and calpain inhibitors. Degradation of wild-type huntingtin by calcium-dependent proteases thus occurs in HD neurons, leading to loss of wild-type huntingtin neuroprotective activity.
Asunto(s)
Calcio/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Calcimicina/farmacología , Calpaína/metabolismo , Sistema Libre de Células , Células Cultivadas , Densitometría , Ácido Glutámico/farmacología , Proteína Huntingtina , Ionóforos/farmacología , Nitrocompuestos , Propionatos/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Gene expression studies conducted with mouse models of Huntington's disease (HD) have revealed profound modifications in gene transcription. However, the complexity of in vivo tissue hampers definition of very early transcriptional modifications and does not allow discrimination between cell-autonomous changes and those resulting from intercellular activity processes. To identify early, cell-autonomous transcriptional changes, we compared gene expression profiles of clonal striata-derived cells expressing different N-terminal 548-amino-acid huntingtin fragments (with 26, 67, 105 or 118 glutamines) under the control of a doxycycline-regulated promoter. In these cells, mutant huntingtin did not form aggregates or cause cell death; therefore, the gene expression profiles report transcriptional changes reflecting early pathogenic events. We found that genes involved in cell signaling, transcription, lipid metabolism and vesicle trafficking were affected, in some cases, within 12 hours of mutant protein induction. Interestingly, this study revealed differential expression of a number of genes involved in cholesterol and fatty acid metabolism, suggesting that these metabolic pathways may play a role in HD pathogenesis.