A Stem Cell-based Assay Platform Demonstrates Alpha-synuclein Dependent Synaptic Dysfunction in Patient-derived Cortical Neurons

Overview

Journal NPJ Parkinsons Dis

Date 2024 May 21

PMID 38773105

Authors

Andrew J White

Karis A Clark

Kellianne D Alexander

Nagendran Ramalingam

Tracy L Young-Pearse

Ulf Dettmer

Dennis J Selkoe

Gary P H Ho

Affiliations

Soon will be listed here.

Abstract

Alpha-synuclein (αS)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB), but whether αS influences synaptic vesicle dynamics in human cortical neurons is unknown. Using a new iPSC-based assay platform for measuring synaptic vesicle cycling, we found that in human cortical glutamatergic neurons, increased αS from either transgenic expression or triplication of the endogenous locus in patient-derived neurons reduced synaptic vesicle cycling under both stimulated and spontaneous conditions. Thus, using a robust, easily adopted assay platform, we show for the first time αS-induced synaptic dysfunction in human cortical neurons, a key cellular substrate for PD dementia and DLB.

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