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| Status |
Public on Apr 13, 2021 |
| Title |
Phenotypic manifestation of alpha-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death
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| Overall design |
RNASeq experiment to compare the SNCA triplication iPSC line (n=3 biological replicates per condition) at baseline and after induction of alpha-synuclein aggregation for 1 and 2 weeks. This was done to investigate whether there are transcriptomic changes upon alpha-synuclein aggregation within neurons using SNCA Triplication line (SFC831-03-03) when compared to their corresponding baseline Non-seeded controls (NSC) using three different types of fibrils: de novo generated fibrils (FIB), MSA amplified Fibrils (MSA) or PD amlpified Fibrils (PD) at 1 microM. A total of 24 different human iPSC samples were sequenced on the Novaseq 6000 platform.
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| Contributor(s) |
Tanudjojo B, Shaikh S, Fenyi A, Bousset L, Agarwal D, Marsh J, Zois C, Herman-Ackah S, Fischer R, Sims D, Melki R, Tofaris GK |
| Citation(s) |
34155194 |
| |
| Submission date |
Apr 13, 2021 |
| Last update date |
Jul 14, 2021 |
| Contact name |
Devika Agarwal |
| E-mail(s) |
devika.agarwal@imm.ox.ac.uk
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| Organization name |
University of Oxford
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| Department |
The MRC Weatherall Institute of molecular medicine
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| Lab |
Centre for Computational Biology
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| Street address |
JR hospital, Headley way
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| City |
Oxford |
| ZIP/Postal code |
OX3 9DS |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA721677 |
| SRA |
SRP314679 |
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