A human striatal-midbrain assembloid model of alpha-synuclein propagation.

Area of Science:

• Neuroscience
• Stem Cell Biology
• Disease Modeling

Background:

• Parkinson's disease (PD) primarily affects humans, limiting animal model utility.
• Human pluripotent stem cells (hPSCs) and neural organoids offer advanced in vitro models for PD research.
• Studying PD etiology requires models that recapitulate human basal ganglia circuitry and pathology.

Purpose of the Study:

• To establish human striatal-midbrain assembloids (hSMAs) from hPSCs.
• To model alpha-synuclein (α-syn) propagation and basal ganglia circuit function in vitro.
• To create a platform for testing therapeutic interventions for PD.

Main Methods:

• Stepwise differentiation of hPSCs into striatal and midbrain organoids.
• Assembly of regionalized organoids into hSMAs to mimic basal ganglia circuits.
• Induction of PD pathology via SNCA overexpression and analysis of α-syn propagation using reporter systems.

Main Results:

• hSMAs successfully recapitulated nigrostriatal and striatonigral pathways with electrophysiologically active neurons.
• Increased α-syn in hSMAs led to nigrostriatal damage and formation of pathological α-syn aggregates and Lewy body-like inclusions.
• Reporter systems confirmed retrograde transport of α-syn to midbrain dopaminergic neurons.
• Pharmacological treatments (Anle138b, Rapamycin) reduced α-syn aggregation in hSMAs.

Conclusions:

• hSMAs represent a novel and effective platform for modeling human PD pathology, including α-syn propagation.
• The model demonstrates key features of PD, such as nigrostriatal damage and Lewy body formation.
• hSMAs provide a valuable tool for investigating PD mechanisms and screening potential therapeutics.