α‐Synuclein Pathology Spreads in a Midbrain–Hindbrain Assembloid Model
Understanding the progression of α-synuclein pathology in neurodegenerative diseases such as Parkinson's disease (PD) is a longstanding challenge. Here, a novel midbrain-hindbrain-assembloid model that recapitulates the spread of α-synuclein pathology observed in PD patients, akin to Braak's hypothesis, is presented. Initially, the presence α-synuclein pathology is demonstrated in the hindbrain organoids. Subsequently, sophisticated tissue engineering methods are employed to create midbrain-hindbrain assembloids. These assembloids allow investigation and description of the spreading of α-synuclein pathology, as it progresses from the hindbrain components to the midbrain regions within the integrated structure. It is observed that an increase in α-synuclein in the hindbrain can induce transfer of the pathology into the healthy midbrain, as well as cause changes at the synapse level. The presented model constitutes a robust in vitro platform for investigating the mechanisms underlying α-synuclein spreading and disease progression, and holding potential for the screening of prospective therapeutics targeting the pathological propagation in PD and related synucleinopathies.
Authors
- Niels Kruse (ORCID: https://orcid.org/0000-0002-4036-8999)
- Graham Robertson (ORCID: https://orcid.org/0000-0002-3841-874X)
- Alise Žagare (ORCID: https://orcid.org/0000-0003-3724-540X)
- Kyriaki Barmpa (ORCID: https://orcid.org/0000-0003-3938-4745)
- Regina Lüttge (ORCID: https://orcid.org/0000-0002-8486-5866)
- Malte Spielmann (ORCID: https://orcid.org/0000-0002-0583-4683)
- Rebecca Matsas (ORCID: https://orcid.org/0000-0002-4027-348X)
- Diana Alejandra Méndez Vega (ORCID: https://orcid.org/0000-0002-6679-7900)
- Rahman Sabahi‐Kaviani (ORCID: https://orcid.org/0000-0003-3534-7218)
- Jens C. Schwamborn (ORCID: https://orcid.org/0000-0003-4496-0559)
- Gemma Gomez‐Giro (ORCID: https://orcid.org/0000-0002-7259-5002)
- Florentia Papastefanaki (ORCID: https://orcid.org/0000-0003-1237-642X)
- Paul Antony (ORCID: https://orcid.org/0000-0002-0450-9301)
- Daniela Frangenberg (ORCID: https://orcid.org/0000-0002-5919-6111)
- Kristian Haendler
Institutions
- University of Luxembourg (LU)
- University Hospital Schleswig-Holstein (DE)
- Pasteur Hellenic Institute (GR)
- Eindhoven University of Technology (NL)
- University of Lübeck (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1002/advs.202409040
- Citations
- 6
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.34
Funders
- H2020 Excellent Science