Characterization of striatal development in Huntington’s Disease and its implication to the adult phenotype
[eng] Huntington's disease (HD) is a devastating neurodegenerative disorder that manifest itself through motor, cognitive and behavioral symptoms. HD is a monogenic disease caused by CAG expansion in the huntingtin gene, which inversely correlates with the age of onset. Despite the ubiquitous e...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223404 |
| Acceso en línea: | https://hdl.handle.net/2445/223404 http://hdl.handle.net/10803/695294 |
| Access Level: | acceso abierto |
| Palabra clave: | Corea de Huntington Neurofisiologia Huntington's chorea Neurophysiology |
| Sumario: | [eng] Huntington's disease (HD) is a devastating neurodegenerative disorder that manifest itself through motor, cognitive and behavioral symptoms. HD is a monogenic disease caused by CAG expansion in the huntingtin gene, which inversely correlates with the age of onset. Despite the ubiquitous expression of mutant huntingtin (mHtt), striatal-projection neurons, known as medium spiny neurons (MSN), are the most vulnerable cell type. Although the onset of the disease has been classically defined by the appearance of motor symptoms, which occur around the age of 40-50, recent studies have shown significant cognitive and mental dysfunction many years before motor onset. A key role of huntingtin in brain development has been described. For this reason and given that the mutation exists from the moment of conception, hypothesis about a possible developmental effect on HD started to emerge. Subtle effects during development can lead to deficiencies in the cellular homeostasis of evolving regional neuronal subpopulations, which in turn can result in adult- onset cell death by normally non-lethal environmental stressors. Neurodegenerative diseases can therefore represent an emerging class of developmental disorders characterized by little developmental abnormalities that cause no obvious deficits. In this thesis we have studied and characterized these developmental alterations in a model of the disease, the zQ175 mouse. Our results show that mouse embryos that have inherited the mutation present a gene expression profile related to the pathophysiology described in adult patients with the disease, from early stages of development. In addition, we have detected that HD developmental alterations are specific to neuronal subpopulation. During the development of the mouse striatum, indirect pathway MSNs (iMSNs) are generated prematurely and excessively during the period of neurogenesis. However, these neurons exacerbately die during the natural period of programmed cell death, which occurs in postnatal stages. Thus, the striatal development of HD mice ends up with a striatum with a lower proportion iMSNs, generating an imbalance between their main neuronal populations. In addition, single-cell analysis allowed us to identify a specific neural progenitor cell (NPC) population differentially affected during HD development. The identification of subtle changes in specific populations of NPCs, and their subsequent follow-up to adults, may clarify neurodevelopmental's contribution to HD. These results suggest that the subtle effects of the mutant huntingtin during development may cause significant alterations that spread to adults and contribute to the most common HD phenotypes. |
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