Neuronal Dysfunction in IPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Overview

Journal J Neurosci

Specialty Neurology

Date 2016 Nov 25

PMID 27881786

Citations 27

Authors

Nancy Stanslowsky

Peter Reinhardt

Hannes Glass

Norman Kalmbach

Maximilian Naujock

Niko Hensel

Verena Lubben

Arun Pal

Anna Venneri

Francesca Lupo

Lucia De Franceschi

Peter Claus

Jared Sterneckert

Alexander Storch

Andreas Hermann

Florian Wegner

Affiliations

Soon will be listed here.

Abstract

Significance Statement: Chorea-acanthocytosis (ChAc) is a fatal neurodegenerative disease without a known cure. To gain pathophysiological insight, we newly established a human in vitro model using skin biopsies from ChAc patients to generate disease-specific induced pluripotent stem cells (iPSCs) and developed an efficient iPSC differentiation protocol providing striatal medium spiny neurons. Using patch-clamp electrophysiology, we detected a pathologically enhanced synaptic activity in ChAc neurons. Healthy control levels of synaptic activity could be restored by treatment of ChAc neurons with the F-actin stabilizer phallacidin and the Src kinase inhibitor PP2. Because Src kinases are involved in bridging the membrane to the actin cytoskeleton by membrane protein phosphorylation, our data suggest an actin-dependent mechanism of this dysfunctional phenotype and potential treatment targets in ChAc.

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