A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived...

Area of Science:

• Neuroscience
• Cell Biology
• Neurodegenerative Diseases

Background:

• Alpha-synuclein (αS) aggregates in Lewy bodies are linked to dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB).
• The direct impact of αS on synaptic vesicle dynamics in human cortical neurons remains largely unexplored.

Purpose of the Study:

• To investigate the effect of increased alpha-synuclein levels on synaptic vesicle cycling in human cortical neurons.
• To establish and utilize a novel induced pluripotent stem cell (iPSC)-based assay for measuring synaptic vesicle dynamics.

Main Methods:

• Developed and employed an iPSC-based assay platform to measure synaptic vesicle cycling.
• Utilized human cortical glutamatergic neurons with either transgenic αS expression or endogenous locus triplication.

Main Results:

• Increased αS levels significantly reduced synaptic vesicle cycling in human cortical neurons.
• This reduction in cycling occurred under both stimulated and spontaneous conditions.
• Demonstrated αS-induced synaptic dysfunction in human cortical neurons.

Conclusions:

• Alpha-synuclein directly impairs synaptic vesicle cycling in human cortical neurons.
• This finding provides a cellular mechanism linking αS pathology to dementia in PD and DLB.
• The developed iPSC-based assay is a robust tool for studying synaptic dysfunction.