According to the World Health Organization (WHO) depression is the leading cause of disability worldwide with more than 300 million patients affected. Current antidepressants have a delayed onset of action and moreover, only two-thirds of patients suffering from depressive disorder respond to antidepressant drug treatment. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of this thesis was to investigate the molecular mechanism of ketamine and its major metabolites at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). As the pathophysiology of depression correlates with decreased adult neurogenesis, I aimed to investigate the molecular effects of ketamine on neural progenitor cell proliferation using a human-based iPSC-model. The findings from this thesis substantially contribute to an enhanced understanding of the molecular mode of action of ketamine as a novel signaling pathway involved in ketamine-induced effects was identified. Ketamine induced proliferation of human iPSC-derived NPCs and bioinformatic analysis of RNA-Seq data revealed significant upregulation of insulin-like growth factor2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 hours after ketamine treatment. In line with this, ketamine dependent proliferation was significantly impaired after IGF2 knockdown. Moreover, ketamine was able to enhance cAMP signaling in NPCs and both, cell proliferation as well as IGF2 expression, were reduced after protein kinase A (PKA)-inhibition. Noteworthy, the Nestin-expressing NPCs do not express functional NMDA receptors, suggesting that the proproliferative effect of ketamine in NPCs is NMDA receptor-independent. Furthermore, 24 hours post administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

No description available.

Zusammenfassung der Arbeit Beteiligung purinerger Rezeptoren am Schmerzgeschehen und an der neuronalen Entwicklung Patrizia Rubini Illes Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig Diese kumulative Arbeit umfasst neun Publikationen, welche die Beteiligung purinerger P2-Rezeptoren (P2R) am Schmerzgeschehen sowie der neuronalen Entwicklung belegen. Im Fokus stehen zwei ATP-aktivierte Rezeptor-Kanäle (P2X3R, P2X7R) und ein G-Protein-gekoppelter, ATP-empfindlicher Rezeptor (P2Y1R). (1) Da sich humane P2X3R an peripheren und zentralen Endigungen primärer-sensorischer Afferenzen befinden, ist die Entschlüsselung der Agonisten-Bindungsstelle für die Entwicklung potenziell analgetisch wirkender, kompetitiver Antagonisten von großer Bedeutung. Wir identifizierten Gruppen konservierter und nicht-konservierter Aminosäure-Reste, die an der Schnittstelle zweier benachbarter Untereinheiten, die Agonisten-Bindungstasche auskleiden. Abhängig vom Mengenverhältnis der zur Transfektion verwendeten cDNA, bilden P2X2-, P2X3- und P2X6-Untereinheiten heteromere Rezeptoren (P2X2/3R, P2X2/6R) in einer variablen Stöchiometrie. (2) Adulte neurale Progenitorzellen (NPZ) der Subventrikulärzone der Maus besitzen Apoptose- bzw. Nekrose-vermittelnde P2X7R. Diese kommen in Assoziation mit P2X4R vor, bilden jedoch wahrscheinlich keinen heteromeren P2X4/7R. P2X7R könnten zum Absterben der, nach metabolischen Schäden im Überschuss gebildeten, NPZ beitragen. Im Laufe der neuronalen Entwicklung verlieren die NPZ ihre P2X7R. Im Gegensatz hierzu bleiben diese bei ihren astrozytären Nachkommen erhalten. (3) Humane mesencephale embryonale NPZ sind mit P2Y1R ausgestattet, die über eine Ca2+-Wellenaktivität die Proliferation der NPZ beschleunigen und in Differenzierungsvorgänge eingreifen. De-differenzierte, kultivierte Neurone des Ratten-Striatum enthalten ebenfalls P2Y1R. Diese setzen Ca2+ aus seinen intrazellulären Speichern frei und öffnen somit Ca2+-selektive „store-operated channels“ in der Zellmembran. Wir konnten zeigen, dass der P2Y1R-stimulierte Anstieg der intrazellulären Ca2+-Konzentration in den striatalen Neuronen durch die Aktivierung von Dopamin D1- und D2R inhibiert wurde. Die vorliegende Arbeit belegt die Bedeutung einiger P2R für zahlreiche, auch potentiell therapeutisch bedeutsame Funktionen des menschlichen und tierischen Organismus.

Um fator relevante para a aceitação de metáforas de mundos virtuais 3D como interfaces homem máquina é a supressão do fator estranheza. Tal fator decorre da percepção de comportamentos não naturais entre as representações de usuários (avatares) e robôs (NPCs Non Playable Characters) nestes ambientes virtuais e acontece, principalmente, devido a diferenças sutís entre o comportamento esperado de um ser humano e o apresentado pelas representações virtuais (avatares). Ao conjunto de comportamentos exibidos denominamos persona. Assim, uma maneira de reduzir a barreira de estranheza entre usuários interagindo em mundos virtuais 3D é fazendo com que suas representações (avatares) tenham personas convincentes. Os seres humanos tem suas personas regidas por seus tratos emocionais. As interações com o ambiente e com outros seres humanos fornecem estímulos que modificam o estado emocional com relação ao estado de equilíbrio e, consequentemente, alteram o comportamento exterior observado. O estado emocional de equilíbrio pode ser obtido através da análise de corpo de comunicação em linguagem natural do usuário. Neste trabalho é defendida a tese de que através da análise do corpo das interações em linguagem natural de usuários nas mídias sociais é possível estabelecer um modelo de personalidade e persona que pode ser transposto para a representação dos usuários nem mundos virtuais 3D, de forma que as representações tenham comportamentos tais que reduzem o fator de estranheza. O modelo faz uso das interações recentes nas mídias sociais e das interações nos mundos virtuais 3D para determinar o estado emocional imediato e o comportamento instantâneo e é coerente com o paradigma do modelo OCC. Também é demonstrado que este modelo é evolutivo: pela análise contínua do corpo da comunicação é acompanhada a evolução da personalidade do usuário, bem como se adequa continuamente sua persona. Os traços de personalidade são analizados no modelo Big Five (Neuroticism, Extraversion, Agreeableness, Conscientiousness, Openness) e operacionalizados no modelo PAD (Personality, arousal, dominance). O modelo constrói um campo de personalidade, no espaço PAD, de tal forma que na ausência de excitação o estado emocional do avatar fica em repouso no centro deste campo. As excitações movimentam o estado ao longo dos eixos PAD e provocam mudanças no comportamento observado. A correspondência entre as mudanças de comportamento do avatar e o movimento do estado do usuário no campo emocional aumenta a concordância entre comportamento esperado e observado, reduzindo o fator de estranheza. / A key factor for the acceptance of 3D virtual world mataphor as human machine interface is the suppression of the strangeness factor, which appears due the perception of non natural behaviour in representations of users (avatars) and bots (NPCs). Such perception raises mostly due to subtle differences in expected behavior for a human being and observed behavior in virtual representations (avatars and NPCs). In this work we will call persona the set of exhibited behaviors. Thus, a way of diminishing the strangeness valley is by supplying avatars with convincing personas. Human beings rule their personas with intermediation of their emotional traits. Interactions with environment and other beings supply stimuli that change the emotional state from the equilibrium situation and, consequently, change observed behavior. Idle emotional state can be determined through natural language communication corpora analysis. In this thesis we state that through the analysis of user interactions in social media it is possible to establish a model of personality and persona that can be transposed to their representation in 3D virtual worlds, so such representation exhibits behavior that minimize strangeness. The model uses recent interations of user in social media and his interactions inside the 3D virtual world to establish current behavior and is coherent with OCC paradigm. It is also demonstrated that such model is evolutive: by the continuous analysis of communication corpora the user personality behavior is updated and its persona is continually adjusted. Personality traits are analysed in the Big Five model (neuroticism, agreeableness, conscientiousness, openness) and operationalized in the PAD model (personality, arousal, dominance). A personality field is built such as in the absence of inputs, emotional state lies in the center of this field. Inputs move state along PAD axes and cause changes in the observed behavior. Correspondence between avatar behavior changes and state changes of user regarding its emotional field enhance the compliance between expected and observed behavior, reducing strangeness.

Um fator relevante para a aceitação de metáforas de mundos virtuais 3D como interfaces homem máquina é a supressão do fator estranheza. Tal fator decorre da percepção de comportamentos não naturais entre as representações de usuários (avatares) e robôs (NPCs Non Playable Characters) nestes ambientes virtuais e acontece, principalmente, devido a diferenças sutís entre o comportamento esperado de um ser humano e o apresentado pelas representações virtuais (avatares). Ao conjunto de comportamentos exibidos denominamos persona. Assim, uma maneira de reduzir a barreira de estranheza entre usuários interagindo em mundos virtuais 3D é fazendo com que suas representações (avatares) tenham personas convincentes. Os seres humanos tem suas personas regidas por seus tratos emocionais. As interações com o ambiente e com outros seres humanos fornecem estímulos que modificam o estado emocional com relação ao estado de equilíbrio e, consequentemente, alteram o comportamento exterior observado. O estado emocional de equilíbrio pode ser obtido através da análise de corpo de comunicação em linguagem natural do usuário. Neste trabalho é defendida a tese de que através da análise do corpo das interações em linguagem natural de usuários nas mídias sociais é possível estabelecer um modelo de personalidade e persona que pode ser transposto para a representação dos usuários nem mundos virtuais 3D, de forma que as representações tenham comportamentos tais que reduzem o fator de estranheza. O modelo faz uso das interações recentes nas mídias sociais e das interações nos mundos virtuais 3D para determinar o estado emocional imediato e o comportamento instantâneo e é coerente com o paradigma do modelo OCC. Também é demonstrado que este modelo é evolutivo: pela análise contínua do corpo da comunicação é acompanhada a evolução da personalidade do usuário, bem como se adequa continuamente sua persona. Os traços de personalidade são analizados no modelo Big Five (Neuroticism, Extraversion, Agreeableness, Conscientiousness, Openness) e operacionalizados no modelo PAD (Personality, arousal, dominance). O modelo constrói um campo de personalidade, no espaço PAD, de tal forma que na ausência de excitação o estado emocional do avatar fica em repouso no centro deste campo. As excitações movimentam o estado ao longo dos eixos PAD e provocam mudanças no comportamento observado. A correspondência entre as mudanças de comportamento do avatar e o movimento do estado do usuário no campo emocional aumenta a concordância entre comportamento esperado e observado, reduzindo o fator de estranheza. / A key factor for the acceptance of 3D virtual world mataphor as human machine interface is the suppression of the strangeness factor, which appears due the perception of non natural behaviour in representations of users (avatars) and bots (NPCs). Such perception raises mostly due to subtle differences in expected behavior for a human being and observed behavior in virtual representations (avatars and NPCs). In this work we will call persona the set of exhibited behaviors. Thus, a way of diminishing the strangeness valley is by supplying avatars with convincing personas. Human beings rule their personas with intermediation of their emotional traits. Interactions with environment and other beings supply stimuli that change the emotional state from the equilibrium situation and, consequently, change observed behavior. Idle emotional state can be determined through natural language communication corpora analysis. In this thesis we state that through the analysis of user interactions in social media it is possible to establish a model of personality and persona that can be transposed to their representation in 3D virtual worlds, so such representation exhibits behavior that minimize strangeness. The model uses recent interations of user in social media and his interactions inside the 3D virtual world to establish current behavior and is coherent with OCC paradigm. It is also demonstrated that such model is evolutive: by the continuous analysis of communication corpora the user personality behavior is updated and its persona is continually adjusted. Personality traits are analysed in the Big Five model (neuroticism, agreeableness, conscientiousness, openness) and operationalized in the PAD model (personality, arousal, dominance). A personality field is built such as in the absence of inputs, emotional state lies in the center of this field. Inputs move state along PAD axes and cause changes in the observed behavior. Correspondence between avatar behavior changes and state changes of user regarding its emotional field enhance the compliance between expected and observed behavior, reducing strangeness.

This is a thesis that deals with the norms and rules of players playing online games together. It is also a thesis about believability, the current capabilities of non-player characters (NPCs) and the attitudes amongst game developers towards dynamic and systemic games AI. The primary theme of this thesis considers which means of communication and coordination in terms of norms and rules are present in groups of players and particularly in guilds and clans playing Massively Multi Online Games (MMOGs) and First Person Shooters (FPSs) respectively. The presence of norms in these types of groups has been overlooked in previous research even though guilds have been addressed to some extent. When rules have been discussed in games research, the actual use, meaning and interpretation behind these rules from a player perspective has been omitted. In this thesis rules and norms are interpreted from a guild and clan perspective as important means for coordination, used in order to keep the group together. The implicit rules are further seen as implicit rules made explicit through guild and clan forums where these groups of players express how to preserve the shared game experience. The absence of rituals, norms and rules has also been studied in temporary groups of one MMOG, with the explanation that existing relations with other players are maintained in these game sessions, but new relations are usually seen as too costly to invest in. The second theme is directed at believability and the state of current NPCs, how immersion is influenced by NPCs that do not act in believable ways. The second theme is also influenced by the first theme, whereby rules and norms are seen as valuable tools for creating believability in NPCs, directly targeting the social layer, a slightly overlooked area of research. The last section is directed at applying the results from the first section, how players play by the rules and norms of the group, and how this could foster believability in NPCs. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 5: In press. Paper 6: In press.</p>

Zusammenfassung der Arbeit Beteiligung purinerger Rezeptoren am Schmerzgeschehen und an der neuronalen Entwicklung Patrizia Rubini Illes Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig Diese kumulative Arbeit umfasst neun Publikationen, welche die Beteiligung purinerger P2-Rezeptoren (P2R) am Schmerzgeschehen sowie der neuronalen Entwicklung belegen. Im Fokus stehen zwei ATP-aktivierte Rezeptor-Kanäle (P2X3R, P2X7R) und ein G-Protein-gekoppelter, ATP-empfindlicher Rezeptor (P2Y1R). (1) Da sich humane P2X3R an peripheren und zentralen Endigungen primärer-sensorischer Afferenzen befinden, ist die Entschlüsselung der Agonisten-Bindungsstelle für die Entwicklung potenziell analgetisch wirkender, kompetitiver Antagonisten von großer Bedeutung. Wir identifizierten Gruppen konservierter und nicht-konservierter Aminosäure-Reste, die an der Schnittstelle zweier benachbarter Untereinheiten, die Agonisten-Bindungstasche auskleiden. Abhängig vom Mengenverhältnis der zur Transfektion verwendeten cDNA, bilden P2X2-, P2X3- und P2X6-Untereinheiten heteromere Rezeptoren (P2X2/3R, P2X2/6R) in einer variablen Stöchiometrie. (2) Adulte neurale Progenitorzellen (NPZ) der Subventrikulärzone der Maus besitzen Apoptose- bzw. Nekrose-vermittelnde P2X7R. Diese kommen in Assoziation mit P2X4R vor, bilden jedoch wahrscheinlich keinen heteromeren P2X4/7R. P2X7R könnten zum Absterben der, nach metabolischen Schäden im Überschuss gebildeten, NPZ beitragen. Im Laufe der neuronalen Entwicklung verlieren die NPZ ihre P2X7R. Im Gegensatz hierzu bleiben diese bei ihren astrozytären Nachkommen erhalten. (3) Humane mesencephale embryonale NPZ sind mit P2Y1R ausgestattet, die über eine Ca2+-Wellenaktivität die Proliferation der NPZ beschleunigen und in Differenzierungsvorgänge eingreifen. De-differenzierte, kultivierte Neurone des Ratten-Striatum enthalten ebenfalls P2Y1R. Diese setzen Ca2+ aus seinen intrazellulären Speichern frei und öffnen somit Ca2+-selektive „store-operated channels“ in der Zellmembran. Wir konnten zeigen, dass der P2Y1R-stimulierte Anstieg der intrazellulären Ca2+-Konzentration in den striatalen Neuronen durch die Aktivierung von Dopamin D1- und D2R inhibiert wurde. Die vorliegende Arbeit belegt die Bedeutung einiger P2R für zahlreiche, auch potentiell therapeutisch bedeutsame Funktionen des menschlichen und tierischen Organismus.:Inhaltsverzeichnis Kapitel Seite Abkürzungen …………………………………………………………………………………. 5 1. Einführung in die Thematik.......................................................................... 7 1.1. Freisetzung von Nukleotiden und ihre Metabolisierung im Extrazellulärraum …7………………………………… 1.2. P2X-Rezeptoren…………………………………………………………………….. 9 1.3. P2Y-Rezeptoren……………………………………………………………………. 12 1.4. P2-Rezeptoren und Schmerz……………………………………………………... 14 1.5. P2-Rezeptoren und neuronale Entwicklung; embryonale undadulte neurale Vorläuferzellen……………………………………………………. 17 1.6. Referenzen………………………………………………………………………….. 19 2. Wissenschaftliche Ergebnisse……………………………………………………… 23 2.1. Komplex I. Struktur-Wirkungs-Zusammenhänge bei rekombinanten, humanen P2X3- und P2X2/3-Rezeptoren in Expressionssystemen…………. 24 2.1.1. Amino acid residues constituting the agonist binding site of the human P2X3 receptor……………………………………………………………… 24 2.1.2. ATP binding site mutagenesis reveals different subunit stoichiometry of functional P2X2/3 and P2X2/6 receptors……………………………………... 26 2.1.3 Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors……………………………………………………………... 28 2.2. Komplex II. Vorhandensein und Wirkung von P2X7-Rezeptoren an kultivierten adulten, neuralen Vorläuferzellen und Astrozyten………….. 29 2.2.1. P2X7 receptors at adult neural progenitor cells of the mouse subventricular zone………………………………………………………………… 29 2.2.2. Co-expression of functional P2X4 and P2X7 receptors at adult neural precursor cells of the mouse subventricular zone……………………… 31 2.2.3. Functional P2X7 receptors at cultured hippocampal astrocytes but not neurons…………………………………………………………………….. 32 2.3. Komplex III. Vorhandensein und Wirkung von P2Y-Rezeptoren an embryonalen neuralen Vorläuferzellen und dedifferenzierten kultivierten striatalenNeuronen... 33 2.3.1. Increase of intracellular Ca2+ by adenine and uracil nucleotides in human midbrain-derived neuronal precursor cells…………... 33 2.3.2. Regulation of intracellular Ca2+ by P2Y1 receptors may depend on the developmental stage of cultured rat striatal neurons…………………... 35 2.3.3. Modulation by D1 and D2 dopamine receptors of ATP-induced release of intracellular Ca2+ in cultured rat striatal neurons 36 3. Zusammenfassung und Ausblick………………………………………… ………... 37 4. Erklärungen, Danksagung…………………………………………… 38 Erklärung über die eigenständige Anfertigung der Arbeit………… 38 Erklärung über den eigenen Anteil an den einzelnen Arbeiten…………….. 39 Danksagung………………………………………………………………… 42

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-04-17T23:12:49Z No. of bitstreams: 1 AngelicaMariaDeSousaLeal_TESE.pdf: 6582579 bytes, checksum: 5f557c13b6008a7677f62167674670fe (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-04-20T22:14:08Z (GMT) No. of bitstreams: 1 AngelicaMariaDeSousaLeal_TESE.pdf: 6582579 bytes, checksum: 5f557c13b6008a7677f62167674670fe (MD5) / Made available in DSpace on 2017-04-20T22:14:08Z (GMT). No. of bitstreams: 1 AngelicaMariaDeSousaLeal_TESE.pdf: 6582579 bytes, checksum: 5f557c13b6008a7677f62167674670fe (MD5) Previous issue date: 2016-09-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / No contexto da resposta ao estresse oxidativo, o reparo por excis?o de bases (BER) ? considerado a principal via para o reparo de les?es oxidadas. Entretanto, estudos indicam o papel do reparo por excis?o de nucleot?deos (NER) na corre??o dessas les?es. Al?m disso, fatores do NER j? tiveram fun??es descritas em outros processos biol?gicos, sendo importante que se busque novas fun??es biol?gicas que possam ser associadas aos fen?tipos das s?ndromes causadas por muta??es nos genes da via NER, dentre elas a Xeroderma pigmentoso grupo de complementa??o A, associada a muta??es em XPA, al?m da s?ndrome de Cockayne, ocasionada por muta??es no gene CSB. Nesse contexto, c?lulas deficientes em XPA (XP12RO) ou CSB (CS1AN) foram submetidas ao estresse oxidativo com per?xido de hidrog?nio (H2O2) e apresentaram um perfil de sensibilidade ao agente, indicando que a aus?ncia dessas prote?nas sensibilizou as linhagens a essa condi??o. A an?lise do transcriptoma de c?lulas XP12RO indicou a diminui??o na express?o de genes com papel na resposta ao dano no DNA e que promovem a sobreviv?ncia celular em resposta ao estresse oxidativo. Nesse cen?rio, os resultados indicaram que XPA pode atuar na regula??o da express?o de genes essenciais ? resposta ao dano no DNA e na sobreviv?ncia ao estresse oxidativo (EGR1, GADD45A, GADD45B e XPC). Por outro lado, a an?lise do transcriptoma de c?lulas CS1AN indicaram a diminui??o na express?o de genes-chave nos processos biol?gicos como transcri??o, processamento de mRNA, prote?lise via ubiquitina-proteassoma ou respira??o celular, indicando um poss?vel papel central da prote?na CSB na regula??o desses processos, em resposta ao estresse oxidativo. Al?m disso, dado o fen?tipo de neurodegenera??o associada a s?ndrome de Cockayne, c?lulas progenitoras neurais (NPCs) e neur?nios derivados de c?lulas-tronco pluripotentes induzidas (iPSCs) deficientes em CSB foram utilizados como modelos de estudo de altera??es neuronais in vitro, de modo que os resultados indicaram que assim como observado nos fibroblastos, c?lulas NPCs deficientes em CSB tamb?m apresentaram sensibilidade a agentes oxidantes. Ainda, os resultados mostraram que assim como observado no transcriptoma de fibroblastos CS1AN, dada a diminui??o na express?o de genes com papel na respira??o celular, as an?lises do consumo de oxig?nio em neur?nios deficientes em CSB indicaram uma poss?vel disfun??o mitocondrial, caracterizada pelo decr?scimo na taxa de consumo de oxig?nio basal e pela diminui??o das capacidades respirat?rias m?xima ou de reserva dessas c?lulas, sugerindo o papel de CSB no metabolismo mitocondrial em ambos os modelos celulares utilizados neste estudo. / In oxidative stress response, the base excision repair (BER) is considered the major pathway for repair of oxidative lesions. However, an increasing number of studies have indicated the role of nucleotide excision (NER) in the repair of these lesions. In addition, some NER factors had functions beyond the role in repair already described and it is important to search for new molecular functions that can be associated to the classical phenotypes of the syndromes caused by mutations in NER genes: Xeroderma pigmentosum complementation group A, caused by mutations in XPA and Cockayne syndrome, caused by mutations in CSB. In this context, XPA (XP12RO) or CSB (CS1AN) deficient cells were submitted to oxidative stress induced by Hydrogen peroxide (H2O2) and the results indicated that both cell lines showed sensitivity to this agent. Furthermore, the transcriptome of XP12RO cells revealed the downregulation of genes that play a role in DNA damage response and promote cell survival in response to oxidative stress. In this scenario, the results indicated that XPA regulates the expression of genes that play a key role in DNA damage response and promote survival in response to stress (EGR1, GADD45A, GADD45B and XPC). On the other hand, the transcriptome analysis of CS1AN cells showed the downregulation of genes that play a key role in biological processes such as transcription, mRNA processing, protein degradation by the ubiquitin?proteasome pathway proteolysis or cellular respiration, indicating a possible role for CSB protein in the regulation of these processes, in response to oxidative stress. In adittion, given the neurodegeneration phenotype associated to Cockayne syndrome, neural progenitor cells (NPCs) and neurons derived from CSB deficient induced pluripotent stem cells (iPSCs) were used as cellular models to analyse neuronal changes in vitro. The results showed that, as observed in fibroblasts CS1AN, NPCs also presented sensitivity to oxidizing agents. Furthermore, as indicated in the transcriptome data from CS1AN fibroblasts, given the downregulation of genes that play a pivotal role in cellular respiration, the analysis of oxygen consumption rates in CSB deficient neurons also indicated a mitochondrial dysfunction characterized by the decrease in oxygen consumption basal rate and a lower maximum respiratory and reserve capacities, suggesting that the lack of functional CSB leads to a mitochondrial dysfunction in both cellular models used in this study. / 2017-12-09