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

Andrew J White; Karis A Clark; Kellianne D Alexander; Nagendran Ramalingam; Tracy L Young-Pearse; Ulf Dettmer; Dennis J Selkoe; Gary P H Ho

doi:10.1038/s41531-024-00725-y

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

NPJ Parkinsons Dis. 2024 May 21;10(1):107. doi: 10.1038/s41531-024-00725-y.

Authors

Andrew J White¹, Karis A Clark¹, Kellianne D Alexander¹, Nagendran Ramalingam¹, Tracy L Young-Pearse¹, Ulf Dettmer¹, Dennis J Selkoe¹, Gary P H Ho²

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
² Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. gho@bwh.harvard.edu.

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.

Abstract

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