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.