Mechanism of spreading of prion and polyglutamine aggregates and role of the cellular prion protein in Huntington’s disease
Identifieur interne : 000705 ( Hal/Corpus ); précédent : 000704; suivant : 000706Mechanism of spreading of prion and polyglutamine aggregates and role of the cellular prion protein in Huntington’s disease
Auteurs : Maddalena CostanzoSource :
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Abstract
The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathies, inherited disorders like Huntington’s disease, and sporadic diseases like Alzheimer’s and Parkinson’s diseases, appear to be directly linked to the formation of fibrillar protein aggregates. For many years, the concept of aggregate spreading and infectivity has been confined to prion diseases. However, recent evidence indicate that both extracellular (e.g. amyloid-β) and intracellular (α- synuclein, tau, huntingtin) amyloidogenic protein are able to move (and possibly replicate) within the brains of affected individuals, thereby contributing to the spread of pathology in a prion-like manner (Brundin et al., 2010; Jucker and Walker, 2011; Aguzzi and Rajendran, 2009). Recently another intriguing connection has been made between prions and other aggregation proteinopathies, as it was suggested that the cellular prion protein, PrPC, whose pathological counterpart is responsible for prion diseases, possibly mediates the toxicity of Aβ, the pathogenic protein in Alzheimer’s disease, and of other β- conformers independently of the propagation of infectious prions (reviewed in Biasini et al., 2012). However, despite the intense research,manyquestionsinprionandnon-prion neurodegenerative diseases are still open regarding both the mechanism of protein aggregate spreading and the mechanism of toxicity. In the first part of my thesis, I contributed to investigate the role of DCs (dendritic cells) in the spreading of prion infection to neuronal cells. I demonstrated that the transfer of PrPSc from DCs (loaded with prion infected brain homogenate) to primary neurons was triggered by direct cell–cell contact and resulted in transmission of infectivity to the co-cultured neurons. These data confirm the possible role of DCs in prion spreading from the periphery to the nervous system. I also provided a plausible transfer mechanism of PrPSc through tunneling nanotubes (TNTs) shown to connect DCs to primary neurons and excluded the involvement of PrPSc secretion in our system. In the second part of my thesis, I investigated the mechanisms of the spreading and toxicity of Htt aggregates and the possible role of PrPC in these events. I demonstrated that Htt aggregates transfer between neuronal cells and primary neurons and that cell-cell contact is required. I also showed the involvement of TNTs in the transfer and reported the aggregation of endogenous wild-type Htt in primary neurons, possibly following the transfer of Htt aggregates. Finally, the last part of my results provides evidences that PrPC is involved in the spreading of the toxicity mediated by mutant Htt in primary neuronal cultures.
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<front><div type="abstract" xml:lang="en">The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathies, inherited disorders like Huntington’s disease, and sporadic diseases like Alzheimer’s and Parkinson’s diseases, appear to be directly linked to the formation of fibrillar protein aggregates. For many years, the concept of aggregate spreading and infectivity has been confined to prion diseases. However, recent evidence indicate that both extracellular (e.g. amyloid-β) and intracellular (α- synuclein, tau, huntingtin) amyloidogenic protein are able to move (and possibly replicate) within the brains of affected individuals, thereby contributing to the spread of pathology in a prion-like manner (Brundin et al., 2010; Jucker and Walker, 2011; Aguzzi and Rajendran, 2009). Recently another intriguing connection has been made between prions and other aggregation proteinopathies, as it was suggested that the cellular prion protein, PrPC, whose pathological counterpart is responsible for prion diseases, possibly mediates the toxicity of Aβ, the pathogenic protein in Alzheimer’s disease, and of other β- conformers independently of the propagation of infectious prions (reviewed in Biasini et al., 2012). However, despite the intense research,manyquestionsinprionandnon-prion neurodegenerative diseases are still open regarding both the mechanism of protein aggregate spreading and the mechanism of toxicity. In the first part of my thesis, I contributed to investigate the role of DCs (dendritic cells) in the spreading of prion infection to neuronal cells. I demonstrated that the transfer of PrPSc from DCs (loaded with prion infected brain homogenate) to primary neurons was triggered by direct cell–cell contact and resulted in transmission of infectivity to the co-cultured neurons. These data confirm the possible role of DCs in prion spreading from the periphery to the nervous system. I also provided a plausible transfer mechanism of PrPSc through tunneling nanotubes (TNTs) shown to connect DCs to primary neurons and excluded the involvement of PrPSc secretion in our system. In the second part of my thesis, I investigated the mechanisms of the spreading and toxicity of Htt aggregates and the possible role of PrPC in these events. I demonstrated that Htt aggregates transfer between neuronal cells and primary neurons and that cell-cell contact is required. I also showed the involvement of TNTs in the transfer and reported the aggregation of endogenous wild-type Htt in primary neurons, possibly following the transfer of Htt aggregates. Finally, the last part of my results provides evidences that PrPC is involved in the spreading of the toxicity mediated by mutant Htt in primary neuronal cultures.</div>
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<abstract xml:lang="en">The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathies, inherited disorders like Huntington’s disease, and sporadic diseases like Alzheimer’s and Parkinson’s diseases, appear to be directly linked to the formation of fibrillar protein aggregates. For many years, the concept of aggregate spreading and infectivity has been confined to prion diseases. However, recent evidence indicate that both extracellular (e.g. amyloid-β) and intracellular (α- synuclein, tau, huntingtin) amyloidogenic protein are able to move (and possibly replicate) within the brains of affected individuals, thereby contributing to the spread of pathology in a prion-like manner (Brundin et al., 2010; Jucker and Walker, 2011; Aguzzi and Rajendran, 2009). Recently another intriguing connection has been made between prions and other aggregation proteinopathies, as it was suggested that the cellular prion protein, PrPC, whose pathological counterpart is responsible for prion diseases, possibly mediates the toxicity of Aβ, the pathogenic protein in Alzheimer’s disease, and of other β- conformers independently of the propagation of infectious prions (reviewed in Biasini et al., 2012). However, despite the intense research,manyquestionsinprionandnon-prion neurodegenerative diseases are still open regarding both the mechanism of protein aggregate spreading and the mechanism of toxicity. In the first part of my thesis, I contributed to investigate the role of DCs (dendritic cells) in the spreading of prion infection to neuronal cells. I demonstrated that the transfer of PrPSc from DCs (loaded with prion infected brain homogenate) to primary neurons was triggered by direct cell–cell contact and resulted in transmission of infectivity to the co-cultured neurons. These data confirm the possible role of DCs in prion spreading from the periphery to the nervous system. I also provided a plausible transfer mechanism of PrPSc through tunneling nanotubes (TNTs) shown to connect DCs to primary neurons and excluded the involvement of PrPSc secretion in our system. In the second part of my thesis, I investigated the mechanisms of the spreading and toxicity of Htt aggregates and the possible role of PrPC in these events. I demonstrated that Htt aggregates transfer between neuronal cells and primary neurons and that cell-cell contact is required. I also showed the involvement of TNTs in the transfer and reported the aggregation of endogenous wild-type Htt in primary neurons, possibly following the transfer of Htt aggregates. Finally, the last part of my results provides evidences that PrPC is involved in the spreading of the toxicity mediated by mutant Htt in primary neuronal cultures.</abstract>
<abstract xml:lang="fr">La pathogénèse de la plupart des maladies neurodégénératives incluant les maladies transmissibles comme les encéphalopathies à prion, les maladies génétiques de type maladie de Huntington et les maladies sporadiques comme les maladies d’Alzheimer et de Parkinson est directement liée à la formation d’agrégats protéiques fibrillaires. Pendant de nombreuses années, le concept de dissémination et d’infectivité de ces agrégats a été réservé aux maladies à prion. Cependant, de récents résultats montrent que ces protéines amyloidiques extracellulaires (β-amyloïde) comme intracellulaires (α-synucléine, tau, huntingtin) sont capables de bouger (et possiblement de se répliquer) d’une zone à l’autre du cerveau à la façon des prions (Brundin et al., 2010; Jucker and Walker, 2011; Aguzzi and Rajendran, 2009). Récemment une nouveau lien a été établie entre prions et différentes protéinopathies à agrégats. Il a été suggéré que le prion cellulaire, PrPC, dont la forme pathologique (PrPSc) est responsable des maladies à prion, pourrait servir de médiateur dans la toxicité de la protéine β-amyloïde impliquée dans la maladie d’Alzheimer comme dans d’autres conformations-β, indépendamment de la propagation des prions infectieux (revue de Biasini et al., 2012). Malgré une intense recherche sur les maladies neurodégénératives à prion ou non, de nombreuses questions restent ouvertes à la fois au niveau du mécanisme de dissémination des agrégats protéiques que du mécanisme de toxicité. Dans la première partie de ma thèse, j’ai contribué à étudier le rôle de cellules dendritiques (DCs) dans la dissémination de l’infection à prion aux neurones. J’ai démontré que le transfert de PrPSc des cellules dendritiques infectées par un homogénat de cerveau infecté par du prion vers les neurones était dû à contact direct entre ces cellules et a pour résultat la transmission de l’infectivité aux neurones en co-culture. Ces résultats confirment le possible rôle des cellules dendritiques dans la propagation du prion de la périphérie vers le système nerveux central. J’ai aussi trouvé un potentiel mécanisme de transfert de PrPSc des cellules dendritiques aux neurones via des nanotubes (TNTs) et exclu l’implication de la sécrétion de PrPSc dans notre système. Dans la seconde partie de ma thèse, j’ai étudié les mécanismes de dissémination et de toxicité des agrégats protéiques huntingtin et le possible rôle de PrPC dans ces évènements. J’ai démontré que les agrégats Htt sont transférés entre les lignées de cellules neuronales et les neurones primaires et qu’un contact direct cellule à cellule est requis. De même, j’ai montré l’implication des TNTs dans ce transfert et l’agrégation des Htt sauvages endogènes dans les neurones primaires, probablement en suivant le transfert des agrégats Htt. La dernière partie de mes résultats montre que PrPC est impliqué dans la propagation de la toxicité induite par les Htt mutants dans des neurones primaires en culture.</abstract>
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