# Phenotypic manifestation of α-synuclein strains derived from Parkinson's disease and multiple system atrophy in human dopaminergic neurons

Article · Tanudjojo B, Shaikh SS, Fenyi A, Bousset L, Agarwal D, Marsh J, Zois C, Heman-Ackah S, Fischer R, Sims D, Melki R, Tofaris GK

- Archive id: doi:10.1038/s41467-021-23682-z
- Published: 2021-06-21
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-021-23682-z
- PMID: 34155194
- PMCID: PMC8217249
- Citations: 79
- Source URL: https://doi.org/10.1038/s41467-021-23682-z
- PDF: https://europepmc.org/articles/PMC8217249/pdf
- Provenance: europepmc

## Abstract

α-Synuclein is critical in the pathogenesis of Parkinson's disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson's disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson's disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson's disease-associated genes influence the phenotypic manifestation of strains in human neurons.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

---
Space Kitty Archive · https://space-kitty.com · API: https://space-kitty.com/api/v1 · MCP: https://space-kitty.com/mcp · Premium: $0.20/request via x402 (Base Sepolia (testnet)). Metadata: arXiv (CC0), OpenAlex (CC0), Europe PMC (CC BY/CC0 works), ClinicalTrials.gov.