Alpha-synuclein pathology transfer in a midbrain-hindbrain assembloid model#

Authors#

Gemma Gomez Giro, Daniela Frangenberg, Daniela Vega, Alise Zagare, Kyriaki Barmpa, Paul Antony, Graham Robertson, Rahman Sabahi-Kaviani, Kristian Haendler, Nathalie Kruse, Florentia Papastefanaki, Rebecca Matsas, Malte Spielman, Regina Luttge, Jens Christian Schwamborn

Abstract#

Understanding the progression of alpha-synuclein pathology in neurodegenerative diseases such as Parkinson’s disease (PD) has been a longstanding challenge. Here, we present a novel midbrain-hindbrain assembloid model that recapitulates the spread of alpha-synuclein pathology observed in PD patients, akin to Braak’s hypothesis. First, we demonstrate alpha-synuclein pathology in the hindbrain organoids. Then, leveraging advanced tissue engineering techniques, we generate midbrain-hindbrain assembloids to characterize the dissemination of alpha-synuclein pathology from the hindbrain to the midbrain regions within the assembloid. We observe that an increase in alpha-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 alpha-synuclein spreading and disease progression, and holding potential for the screening of prospective therapeutics targeting the pathological propagation in PD and related synucleinopathies.