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Mutant Protein Spread in Huntington's Disease and Its Implications for Other Neurodegenerative Disorders of the CNS

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Mutant Protein Spread in Huntington's Disease and Its Implications for Other Neurodegenerative Disorders of the CNS Mutant protein spread in Huntington's disease and its implications for other neurodegenerative disorders of the CNS Thèse Alexander Maxan Doctorat en neurobiologie Philosophiæ doctor (Ph. D.) Québec, Canada © Alexander Maxan, 2020 Mutant protein spread in Huntington’s disease and its implications for other neurodegenerative disorders of the CNS Thèse Alexander Maxan Sous la direction de : Dre Francesca Cicchetti, directrice de recherche Résumé La maladie de Huntington (MH) est une maladie génétique dégénérative du système nerveux central (SNC), laquelle se caractérise par une expansion du triplet nucléotidique CAG dans l'exon 1 du gène huntingtine. Cette expansion entraîne la production d’une protéine huntingtine mutée, la mHTT. Cliniquement, la pathologie se manifeste par une variété de symptômes, notamment des problèmes psychiatriques et cognitifs ainsi que des déficits moteurs. Au niveau cellulaire, une atrophie sévère du striatum résulte d'une perte neuronale majeure, laquelle se produit initialement dans le noyau caudé et implique ensuite le putamen. La nature génétique de la MH permet un diagnostic précoce, avant même l’apparition des premiers symptômes. Malgré cela, aucune thérapie neuroprotectrice ou modifiant la maladie ne s’est révélée efficace. Plusieurs essais cliniques de transplantations cellulaires ont été intentés, mais aucun soulagement symptomatique significatif n'a été signalé à ce jour. D’autre part, l'évaluation post-mortem du cerveau de ces patients nous a permis d'identifier des agrégats de mHTT dans le tissu greffé, suggérant que la protéine pourrait être capable de se propager des cellules hôtes aux cellules – pourtant génétiquement saines – du transplant. Nous avons alors émis l'hypothèse que le produit génique anormal, la mHTT, pourrait se propager de cellule à cellule après son introduction dans le cerveau et absorption neuronale. Cette hypothèse a déjà été étayée par de nombreuses publications démontrant les conséquences de la propagation de protéines pathologiques, telles que l’amyloïde β, tau et α- synucléine (α-syn) dans d'autres troubles neurodégénératifs. Dans le cas de la MH, la recherche a été en mesure d'observer ce phénomène in vitro. Au cours de mon doctorat, nous avons entrepris pour la première fois d'évaluer les effets de la propagation de la mHTT in vivo. J’ai tout d’abord pu réaliser l’évaluation post-mortem d'un cerveau de patient atteint de la MH. Je me suis ensuite intéressé à l’étude des conséquences de l'introduction de différents intermédiaires agrégés de la protéine dans le cerveau de différents modèles animaux de la MH (souris et primates non humains). Ces différents protocoles m’ont ainsi permis d'examiner 1- les possibilités d’induire des phénotypes de type MH chez des animaux génétiquement sains, et 2- la capacité à accélérer l’apparition du phénotype chez des modèles transgéniques de la maladie. Pour cela, nous avons administré différentes sources de mHTT – provenant notamment de patients MH, des fibrilles de mHTT exogènes ou encore via l’utilisation d’un virus adéno-associé (AAV) de mHTT – à des souris et des primates non humains. Nos résultats suggèrent fortement que la mHTT peut être libérée dans l’environnement cellulaire. Par la suite, la protéine mutée peut être assimilée par les cellules voisines. Dans le développement de futures thérapies, cette fenêtre de temps entre la libération de la mHTT et sa réabsorption peut se révéler particulièrement opportune pour cibler la protéine mutée. En effet, en ciblant la mHTT extracellulaire, ceci permettrait de réduire la propagation de la protéine et les effets sous-jacents de cette propagation. ii Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is characterized by a CAG expansion in exon 1 of the huntingtin gene. This expansion results in the production of mutant huntingtin (mHTT). Clinically, the disease presents a variety of symptoms including psychiatric and cognitive problems in addition to motor disabilities. Neuropathologically, severe atrophy of the striatum results from neuronal loss, which initially occurs in the caudate nucleus and subsequently involves the putamen. The genetic nature of HD allows it to e diagnosed before any signs are observable. Despite this, no effective neuroprotective or disease-modifying therapies have emerged as efficient treatments. My PhD thesis included post-mortem evaluation of an HD patient, but largely focused on introducing different aggregate intermediates of the protein into the brains of mice and non-human primates in order to examine if we can create HD-like phenotypes in wild-type (WT) animals, or if we could accelerate phenotype appearance in transgenic models of the disease. Finally, we hypothesized that the abnormal gene product, mHTT could spread from cell- to-cell following introduction to the brain and neuronal uptake. This has previously been supported by numerous publications demonstrating the consequences of abnormal protein propagation, such as amyloid β, tau and α- synuclein (α-syn) in other neurodegenerative disorders. Research has also been able to examine this phenomenon in vitro, however we set out for the first time to examine the effects of purified mHTT derived from patients, exogenous mHTT fibrils, and an adeno-associated vector delivery of mHTT on the brains of mice and non-human primates. Our results strongly suggest that mHTT can be released and taken up by cells and that this window of time may be opportune for targeting the protein in future therapies. While many current treatments undergoing testing involve lowering the amount of mHTT produced by the gene, these forms of therapies would require treatment extremely early in life as by adulthood, mHTT is already plentiful in the brain. Others aim to target intracellular mHTT, however this fails to acknowledge the importance of extracellular forms of the protein. Thus, the use of antibodies is an interesting avenue to explore. Indeed, these, by targeting the extracellular mHTT, we could reduce the spread of the protein and the underlying effects of this spread. iii Table of contents Résumé ........................................................................................................................................................ ii Abstract ........................................................................................................................................................ iii Table of contents ......................................................................................................................................... iv List of figures ............................................................................................................................................... ix List of tables ................................................................................................................................................ xi List of abbreviations ..................................................................................................................................... xii Acknowledgements ..................................................................................................................................... xv Avant-propos .............................................................................................................................................. xvi Introduction................................................................................................................................................... 1 1. Huntington’s disease ............................................................................................................................. 1 2. Symptomatology ................................................................................................................................... 1 3. Neuropathology .................................................................................................................................... 2 4. Proteins in neurodegenerative disorders ................................................................................................ 4 5. The normal form of the HTT protein ....................................................................................................... 4 6. The mutated form ................................................................................................................................. 5 7. Gain vs. loss of function ........................................................................................................................ 7 8. Animal models ...................................................................................................................................... 8 9. Transcellular propagation .................................................................................................................... 10 10. Transynaptic propagation .................................................................................................................. 13 11. Hematogenous transport of mHTT through the BBB ........................................................................... 16 12. Treating HD ...................................................................................................................................... 17 13. Current pharmacological treatments .................................................................................................. 19 14. New avenues of treatment ................................................................................................................
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