Reference : DISSECTING GENETIC EPISTASIS IN FAMILIAL PARKINSON’S DISEASE USING A DIGENIC PATIENT-...
Dissertations and theses : Doctoral thesis
Life sciences : Biochemistry, biophysics & molecular biology
Life sciences : Genetics & genetic processes
Human health sciences : Multidisciplinary, general & others
Systems Biomedicine
http://hdl.handle.net/10993/40586
DISSECTING GENETIC EPISTASIS IN FAMILIAL PARKINSON’S DISEASE USING A DIGENIC PATIENT-DERIVED STEM CELL MODEL
English
Hanss, Zoé mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > > ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)]
13-Sep-2019
University of Luxembourg, ​​Luxembourg
Docteur en Biologie
189
Krüger, Rejko mailto
[en] iPSC ; Glucocerebrosidase ; Parkin ; alpha-synuclein ; CRISPR-Cas9
[en] Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. 10% of PD patients present a familial form of the disease implicating genetic mutations. A variability in terms of disease expressivity, severity and penetrance can be observed among familial cases. The idea that the classical one-gene one-trait model may not catch the full picture of genetic contribution to PD pathophysiology is increasingly recognized. Therefore, a polygenic model where multiple genes would influence the disease risk and the phenotypic traits in PD should be investigated. Mutations in PRKN, encoding the E3 ubiquitin-protein ligase Parkin, cause young onset autosomal recessive forms of PD. A variability in terms of clinical presentation and neuropathology have been observed in PD patients carrying mutations in Parkin. On the other hand, mutations in GBA were recently recognized as the most common genetic risk factor for developing PD. The incomplete penetrance of the disease in patients with GBA mutations may implicate other genetic factors. Therefore, it can be hypothesized that the interactions between common PD genes like PRKN and GBA can contribute to the phenotypic heterogeneity observed in PD cases. To explore this hypothesis, we generated patient-derived cellular models from several PD patients carrying pathogenic mutations in either both PRKN and GBA (triallelic models) or in only one of them (bi- or monoallelic models). We developed a novel strategy to gene edit the N370S mutation in GBA via CRISPR-Cas9, without interference with its respective pseudogene, which allows for the dissection of the role of GBA in the context of a PRKN mutation on an isogenic background. We identified a specific α-synuclein homeostasis in the triallelic model. The genetic and pharmacological rescue of GBA in the triallelic model modified the observed α-synuclein phenotype, proving the contribution of GBA to the observed phenotype. We then investigated whether Parkin was contributing to the phenotype. The modulation of Parkin function in the context of a GBA mutation induced a modification of the α-synuclein homeostasis. We therefore concluded that both PRKN and GBA are influencing α-synuclein homeostasis in the triallelic model. Nevertheless, the phenotypic outcome of the co-occurrence of these mutations was not additive nor synergistic. We therefore suggest the existence of an epistatic interaction between mutant GCase and Parkin that would underlie the clinical heterogeneity observed in PD patients carrying these mutations.
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Fonds National de la Recherche - FnR
Researchers ; Students
http://hdl.handle.net/10993/40586
H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR ; FNR6682797 > Rejko Krüger > Endophenotypes in Neurodegeneration > Comprehensive assessment of endophenotypes in neurodegenerative diseases - translating impaired molecular signalling pathways into novel therapeutic strategies for Parkinson’s disease > 01/06/2014 > 31/05/2019 > 2013

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Limited access
PhD_Thesis_Hanss_PhD-FSTC-2019-53.pdfAuthor postprint7.03 MBRequest a copy

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.