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Open AccessArticle

Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis

1
Section for Translational Neurodegeneration “Albrecht Kossel”, Department of Neurology, Universitätsmedizin Rostock, 18057 Rostock, Germany
2
Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
3
Department of Neurology, Städtisches Klinikum Dresden, 01129 Dresden, Germany
4
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany
5
AbbVie Deutschland GmbH & Co KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
6
Department of Neurology, University of Rostock, 18147 Rostock, Germany
7
German Center for Neurodegenerative Diseases (DZNE) Rostock, 18147 Rostock, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1797; https://doi.org/10.3390/ijms21051797
Received: 30 January 2020 / Revised: 27 February 2020 / Accepted: 3 March 2020 / Published: 5 March 2020
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lyn-kinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease. View Full-Text
Keywords: organelle trafficking; human induced pluripotent stem cells (iPSC); Chorea Acanthocytosis (ChAc); microfluidic chambers (MFCs); lysosomes; mitochondria; motoneurons (MN) organelle trafficking; human induced pluripotent stem cells (iPSC); Chorea Acanthocytosis (ChAc); microfluidic chambers (MFCs); lysosomes; mitochondria; motoneurons (MN)
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MDPI and ACS Style

Glaß, H.; Neumann, P.; Pal, A.; Reinhardt, P.; Storch, A.; Sterneckert, J.; Hermann, A. Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis. Int. J. Mol. Sci. 2020, 21, 1797. https://doi.org/10.3390/ijms21051797

AMA Style

Glaß H, Neumann P, Pal A, Reinhardt P, Storch A, Sterneckert J, Hermann A. Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis. International Journal of Molecular Sciences. 2020; 21(5):1797. https://doi.org/10.3390/ijms21051797

Chicago/Turabian Style

Glaß, Hannes; Neumann, Patrick; Pal, Arun; Reinhardt, Peter; Storch, Alexander; Sterneckert, Jared; Hermann, Andreas. 2020. "Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis" Int. J. Mol. Sci. 21, no. 5: 1797. https://doi.org/10.3390/ijms21051797

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