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Activation of FADD-Dependent neuronal death pathways as a predictor of pathogenicity for LRRK2 mutations
dc.creator | Melachroinou K., Leandrou E., Valkimadi P.-E., Memou A., Hadjigeorgiou G., Stefanis L., Rideout H.J. | en |
dc.date.accessioned | 2023-01-31T08:58:37Z | |
dc.date.available | 2023-01-31T08:58:37Z | |
dc.date.issued | 2016 | |
dc.identifier | 10.1371/journal.pone.0166053 | |
dc.identifier.issn | 19326203 | |
dc.identifier.uri | http://hdl.handle.net/11615/76491 | |
dc.description.abstract | Background Despite the plethora of sequence variants in LRRK2, only a few clearly segregate with PD. Even within this group of pathogenic mutations, the phenotypic profile can differ widely. Objective We examined multiple properties of LRRK2 behavior in cellular models over-expressing three sequence variants described in Greek PD patients in comparison to several known pathogenic and non-pathogenic LRRK2 mutations, to determine if specific phenotypes associated with pathogenic LRRK2 can be observed in other less-common sequence variants for which pathogenicity is unclear based on clinical and/or genetic data alone. Methods The oligomerization, activity, phosphorylation, and interaction with FADD was assessed in HEK293T cells over-expressing LRRK2; while the induction of neuronal death was determined by quantifying apoptotic nuclei in primary neurons transiently expressing LRRK2. Results One LRRK2 variant, A211V, exhibited a modest increase in kinase activity, whereas only the pathogenic mutants G2019S and I2020T displayed significantly altered auto-phosphorylation. We observed an induction of detergent-insoluble high molecular weight structures upon expression of pathogenic LRRK2 mutants, but not the other LRRK2 variants. In contrast, each of the variants tested induced apoptotic death of cultured neurons similar to pathogenic LRRK2 in a FADD-dependent manner. © 2016 Melachroinou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | en |
dc.language.iso | en | en |
dc.source | PLoS ONE | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84994469017&doi=10.1371%2fjournal.pone.0166053&partnerID=40&md5=2118b1a8cff2cb157af58b0589f77144 | |
dc.subject | Fas associated death domain protein | en |
dc.subject | leucine rich repeat kinase 2 | en |
dc.subject | FADD protein, human | en |
dc.subject | Fas associated death domain protein | en |
dc.subject | guanosine triphosphate | en |
dc.subject | leucine rich repeat kinase 2 | en |
dc.subject | LRRK2 protein, human | en |
dc.subject | animal cell | en |
dc.subject | animal tissue | en |
dc.subject | apoptosis | en |
dc.subject | Article | en |
dc.subject | cell death | en |
dc.subject | controlled study | en |
dc.subject | embryo | en |
dc.subject | enzyme activation | en |
dc.subject | gene | en |
dc.subject | gene expression | en |
dc.subject | gene function | en |
dc.subject | gene interaction | en |
dc.subject | gene mutation | en |
dc.subject | gene structure | en |
dc.subject | genetic variability | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | LRRK2 gene | en |
dc.subject | nerve cell | en |
dc.subject | nonhuman | en |
dc.subject | oligomerization | en |
dc.subject | pathogenicity | en |
dc.subject | protein binding | en |
dc.subject | protein expression | en |
dc.subject | protein function | en |
dc.subject | protein interaction | en |
dc.subject | protein phosphorylation | en |
dc.subject | rat | en |
dc.subject | sequence analysis | en |
dc.subject | size exclusion chromatography | en |
dc.subject | Western blotting | en |
dc.subject | cell culture | en |
dc.subject | cell line | en |
dc.subject | genetics | en |
dc.subject | HEK293 cell line | en |
dc.subject | metabolism | en |
dc.subject | mutation | en |
dc.subject | Parkinson disease | en |
dc.subject | pathology | en |
dc.subject | phosphorylation | en |
dc.subject | protein protein interaction | en |
dc.subject | signal transduction | en |
dc.subject | Cell Death | en |
dc.subject | Cell Line | en |
dc.subject | Cells, Cultured | en |
dc.subject | Fas-Associated Death Domain Protein | en |
dc.subject | Guanosine Triphosphate | en |
dc.subject | HEK293 Cells | en |
dc.subject | Humans | en |
dc.subject | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | en |
dc.subject | Mutation | en |
dc.subject | Neurons | en |
dc.subject | Parkinson Disease | en |
dc.subject | Phosphorylation | en |
dc.subject | Protein Interaction Maps | en |
dc.subject | Signal Transduction | en |
dc.subject | Public Library of Science | en |
dc.title | Activation of FADD-Dependent neuronal death pathways as a predictor of pathogenicity for LRRK2 mutations | en |
dc.type | journalArticle | en |
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