رسالة جامعية
Clinical aspects and in vitro modelling of GBA1 variant-associated Parkinson's disease
| العنوان: | Clinical aspects and in vitro modelling of GBA1 variant-associated Parkinson's disease |
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| المؤلفون: | Stoker, Thomas Benjamin |
| بيانات النشر: | Robinson College Department of Clinical Neuroscience University of Cambridge |
| سنة النشر: | 2020 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Parksinson's disease, GBA1, Induced neurons, Cell reprogramming, Trehalose, Nortriptyline |
| الوصف: | Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterised by a typical movement disorder, accompanied by a number of non-motor manifestations including cognitive impairment, neuropsychiatric symptoms, autonomic features and sleep disturbance. The aetiology of PD is incompletely understood, but there has been growing interest in the role of genetic risk factors contributing to the development of PD. Mutations in the GBA1 gene have been identified as numerically the most important in PD, being found in approximately 5 % to 10 % of patients, and increasing the risk of developing PD by up to 20- to 30-fold. However, there is correlation between the severity of the genetic variant and the degree to which PD risk is increased, with milder variants only increasing the risk by approximately two-fold. Furthermore, as well as being relatively common, GBA1 mutations have also been reported to adversely affect prognosis, in terms of motor progression and risk of dementia, though questions remain about the incidence of these outcomes and the contribution of “non-pathogenic” variants in the GBA1 gene. GBA1 mutation-associated PD (GBA1-PD) therefore constitutes an important subgroup of the PD population, and one in which novel therapies could significantly reduce the burden of PD. The pathogenesis of GBA1-PD seems to be related to dysfunction of the lysosome-autophagy system, making this system a prime therapeutic target in this group. This project consists of a combined epidemiological and in vitro study of GBA1-PD, with a focus on better characterisation of the clinical aspects of GBA1-PD, and establishing a novel disease model using directly reprogrammed induced neurons (iNs) in which to test putative disease-modifying treatments. Firstly, long-term data from two incident PD clinical cohorts is presented, which constitutes the longest follow-up study of GBA1-PD to date. Consistent with previous studies, GBA1 abnormalities were found to increase the risk of dementia and motor progression, ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/301989Test |
| DOI: | 10.17863/CAM.49065 |
| الإتاحة: | https://doi.org/10.17863/CAM.49065Test https://www.repository.cam.ac.uk/handle/1810/301989Test |
| حقوق: | All rights reserved ; https://www.rioxx.net/licenses/all-rights-reservedTest/ |
| رقم الانضمام: | edsbas.DD51D72F |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.49065 |
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