Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/118463
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Consiglio, Antonella | - |
dc.contributor.advisor | Raya Chamorro, Ángel | - |
dc.contributor.author | Calatayud Aristoy, Carles | - |
dc.contributor.other | Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació | - |
dc.date.accessioned | 2017-12-04T11:03:21Z | - |
dc.date.available | 2018-03-14T23:01:24Z | - |
dc.date.issued | 2017-09-14 | - |
dc.identifier.uri | http://hdl.handle.net/2445/118463 | - |
dc.description.abstract | [eng] Despite the advances in the identification of genes and proteins involved in Parkinson’s disease (PD), there are still appreciable gaps in our understanding of the mechanisms underlying the chronic neurodegenerative process in PD. In the lab, it has been demonstrated that iPSC technology can be used to observe phenotypes relevant to neurodegeneration in PD, and also provided first proof-of-principle evidence that neurons with the genome of a sporadic PD patient exhibited similar phenotypes as seen in iPSC derived from patients with monogenic LRRK2 (G2019S) PD. In the present study we generated a complementary set of iPSC lines from asymptomatic individuals carrying pathogenic LRRK2 mutations, whose gene pool may have a prevailing protective effect. We then corrected the LRRK2 mutation by using TALEN-mediated genetic engineering in the symptomatic LRRK2-iPSC lines, as well as well as introduced it in our already established control-iPSC lines. Dopaminergic neurons differentiated in parallel from this subset of iPSC lines have been cultured over a long time span and monitored for the appearance of neurodegeneration phenotypes (including reduced numbers of neurites and neurite arborization and α-synuclein accumulation) after 75 days in culture. Interestingly we found that while PD iPSC-derived DA neurons showed altered morphology and shorter/fewer neurites, DAn derived from NMC show mature morphology and long neurites with complex arborization, similar to those differentiated from Ctrl-iPSC. We have also identified mutation-linked phenotypes such as α-synuclein accumulation whose appearance was delayed in NMC neurons compared to LRRK2-PD neurons. Complementarily, we have sequenced the exome of our cohort in order to identify the genetic modifiers of LRRK2 mutation penetrance. Importantly, the availability of a refined set of PD patient-specific iPSC lines representing symptomatic and asymptomatic cases of familial PD sharing the same pathogenic mutation in LRRK2, as well as isogenic iPSC lines in which the mutation has been edited out, will open a new window for the early diagnosis and individualized treatment of the prodromic period of the disease. | - |
dc.format.extent | 238 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Universitat de Barcelona | - |
dc.rights | (c) Calatayud, 2017 | - |
dc.source | Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació | - |
dc.subject.classification | Malaltia de Parkinson | - |
dc.subject.classification | Ciències de la salut | - |
dc.subject.classification | Enginyeria genètica | - |
dc.subject.other | Parkinson's disease | - |
dc.subject.other | Medical sciences | - |
dc.subject.other | Genetic engineering | - |
dc.title | Investigating the genetic component of Parkinson’s disease through the use of human induced pluripotent stem cells and gene editing | - |
dc.type | info:eu-repo/semantics/doctoralThesis | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2017-12-04T11:03:22Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.tdx | http://hdl.handle.net/10803/457667 | - |
Appears in Collections: | Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
CCA_PhD_THESIS.pdf | 49.59 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.