Modeling Synucleinopathy Using hESC-Derived Cerebral Organoids

Area of Science:

• Neuroscience
• Stem Cell Biology
• Genetics

Background:

• Synucleinopathies like Parkinson's disease are challenging to model in humans.
• Existing animal and cellular models have limitations in replicating human brain pathology.

Purpose of the Study:

• To develop a human cerebral organoid (CO) model for synucleinopathy.
• To investigate the utility of this model for therapeutic drug screening.

Main Methods:

• Generated human cerebral organoids (COs) from a human embryonic stem cell (hESC) line overexpressing the Ala53Thr mutation in SNCA (SNCA^A53T).
• Characterized A53T COs for alpha-synuclein (α-Syn) expression, phosphorylation, aggregation, tau pathology, and amyloid-beta levels.
• Treated A53T COs with Synuclean D (SynD), an α-Syn aggregation inhibitor, to assess therapeutic efficacy.

Main Results:

• A53T COs exhibited elevated α-Syn expression, increased α-Syn phosphorylation, and Lewy body-like aggregates.
• Increased phosphorylated tau and neurofibrillary tangle-like deposits were observed, while amyloid-beta remained unchanged.
• SynD treatment significantly reduced α-Syn and tau phosphorylation without altering total α-Syn levels.

Conclusions:

• Established a robust hESC-derived synucleinopathy CO model with the SNCA^A53T mutation.
• Demonstrated the model's potential as a valuable tool for screening therapeutics for synucleinopathies.