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Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization
- Source :
- The journal of neuroscience 36(47), 12027-12043 (2016). doi:10.1523/JNEUROSCI.0456-16.2016
- Publication Year :
- 2016
-
Abstract
- Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration. Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology, we established a ChAc patient-derived induced pluripotent stem cell model and an efficient differentiation protocol providing a large population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc. Patient-derived MSNs displayed enhanced neurite outgrowth and ramification, whereas synaptic density was similar to controls. Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs. Treatment with the F-actin stabilizer phallacidin or the Src kinase inhibitor PP2 resulted in the significant reduction of disinhibited synaptic currents to healthy control levels, suggesting a Src kinase- and actin-dependent mechanism. This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs. These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function.SIGNIFICANCE STATEMENTChorea-acanthocytosis (ChAc) is a fatal neurodegenerative disease without a known cure. To gain pathophysiological insight, we newly established a humanin vitromodel 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.
- Subjects :
- 0301 basic medicine
metabolism [GABAergic Neurons]
actin cytoskeleton
striatal medium spiny neurons
Synaptic Transmission
0302 clinical medicine
metabolism [Neuroacanthocytosis]
metabolism [src-Family Kinases]
GABAergic Neurons
Induced pluripotent stem cell
Research Articles
Cells, Cultured
Neurons
Kinase
patch-clamp electrophysiology
General Neuroscience
Neurodegeneration
Cell Differentiation
Src kinase
chorea-acanthocytosis
human induced pluripotent stem cells
pathology [Induced Pluripotent Stem Cells]
Cell biology
metabolism [Induced Pluripotent Stem Cells]
antagonists & inhibitors [src-Family Kinases]
src-Family Kinases
Female
Neuroacanthocytosis
Proto-oncogene tyrosine-protein kinase Src
Adult
pathology [Corpus Striatum]
Neurite
metabolism [Actins]
Induced Pluripotent Stem Cells
Biology
Medium spiny neuron
03 medical and health sciences
LYN
medicine
Humans
ddc:610
metabolism [Corpus Striatum]
medicine.disease
Actin cytoskeleton
Corpus Striatum
Actins
030104 developmental biology
pathology [GABAergic Neurons]
Neuroscience
030217 neurology & neurosurgery
pathology [Neuroacanthocytosis]
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The journal of neuroscience 36(47), 12027-12043 (2016). doi:10.1523/JNEUROSCI.0456-16.2016
- Accession number :
- edsair.doi.dedup.....d2f8577f2b85958466c1ea72bfe83f55