Clinical aspects and in vitro modelling of GBA1 variant-associated Parkinson's disease
Creators: name: Stoker, Thomas Benjamin
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Parksinson's disease
GBA1
Induced neurons
Cell reprogramming
Trehalose
Nortriptyline

description: 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, and also to increase the risk of death – an outcome which few studies have previously reported on. Additionally, it was found that carrying “non-pathogenic” GBA1 variants also adversely affected disease course. In order to set up a novel drug-screening model, iNs were generated from healthy controls, and PD patients with and without GBA1 abnormalities. The use of iNs means that the age signature is preserved in the cells, such that they retain factors potentially important in pathogenesis, that are lost in similar in vitro models in which induced pluripotent stem cell-derived neurons are employed. The iNs were treated with pre-formed fibrils of pathogenic α-synuclein to induce formation of α-synuclein aggregates, which were formed in greater numbers in diseased cell lines compared to healthy controls. Additionally, PD iNs in particular developed a reduction in mitochondrial membrane potential following treatment with PFFs, suggesting that they were more susceptible to relevant downstream pathology. This system was then used to study the effects of two drugs previously suggested to enhance activity in the lysosome-autophagy system – trehalose and nortriptyline. Trehalose was found to alter autophagy activity in carriers and non-carriers of GBA1 mutations, which resulted in a reduction in α-synuclein-induced pathology. In contrast, nortriptyline was ineffective in GBA1-PD patient-derived neurons, suggesting that it is not able to overcome the autophagy dysfunction seen in this subgroup, but was able to reduce pathology in PD patient cells without GBA1 abnormalities. In conclusion, this project describes the long-term clinical course in GBA1-PD, as well as a novel in vitro model for studying pathogenesis and drug-screening in this PD patient group. Two drugs tested were identified to reduce pathology in different PD subgroups, highlighting the power of this work to the future development of personalised therapies for PD.
description: This work was funded by the Cure Parkinson's Trust