{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:27:06Z","timestamp":1791462426284,"version":"4.3.4"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["FKZ:01GM1303"],"award-info":[{"award-number":["FKZ:01GM1303"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG FZT 111"],"award-info":[{"award-number":["DFG FZT 111"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG EXC 168"],"award-info":[{"award-number":["DFG EXC 168"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hermann and Lilly Schilling-Stiftung f\u00fcr medizinische Forschung im Stifterverband","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/100012178","name":"Advocacy for Neuroacanthocytosis Patients","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/100012178","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms21051797","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T09:26:41Z","timestamp":1583486801000},"page":"1797","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis"],"prefix":"10.3390","volume":"21","author":[{"given":"Hannes","family":"Gla\u00df","sequence":"first","affiliation":[{"name":"Section for Translational Neurodegeneration \u201cAlbrecht Kossel\u201d, Department of Neurology, Universit\u00e4tsmedizin Rostock, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Neumann","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative Diseases, Department of Neurology, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"Department of Neurology, St\u00e4dtisches Klinikum Dresden, 01129 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Pal","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative Diseases, Department of Neurology, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Center for Regenerative Therapies Dresden (CRTD), Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"AbbVie Deutschland GmbH &amp; Co KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Storch","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rostock, 18147 Rostock, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Sterneckert","sequence":"additional","affiliation":[{"name":"Department of Neurology, St\u00e4dtisches Klinikum Dresden, 01129 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-7791","authenticated-orcid":false,"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[{"name":"Section for Translational Neurodegeneration \u201cAlbrecht Kossel\u201d, Department of Neurology, Universit\u00e4tsmedizin Rostock, 18057 Rostock, Germany"},{"name":"Division of Neurodegenerative Diseases, Department of Neurology, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"Center for Regenerative Therapies Dresden (CRTD), Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/B978-0-444-52014-2.00007-0","article-title":"Neuroacanthocytosis","volume":"100","author":"Walker","year":"2011","journal-title":"Handb. Clin. Neurol."},{"key":"ref_2","unstructured":"Maglott, D., Landrum, M., Church, D., Lee, J.M., Riley, G., Jang, W., and Rubinstein, W. (2020, March 05). ClinVar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?term=VPS13A%5Bgene%5D."},{"key":"ref_3","unstructured":"Pagon, R.A., and Ardinger, H.H. (2014). Chorea-Acanthocytosis. Chorea Causes and Management, University of Washington."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Walker, R.H., Danek, A., and Saiki, S. (2008). Neuroacanthocytosis Syndromes II, Springer-Verlag. [1st ed.]. SpringerLink (Online service).","DOI":"10.1007\/978-3-540-71693-8"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9075","DOI":"10.1073\/pnas.83.23.9075","article-title":"Isolation of yeast mutants defective in protein targeting to the vacuole","volume":"83","author":"Bankaitis","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","first-page":"3004","article-title":"VPS13 regulates membrane morphogenesis during sporulation in Saccharomyces cerevisiae","volume":"125","author":"Park","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1091\/mbc.e16-02-0112","article-title":"Yeast Vps13 promotes mitochondrial function and is localized at membrane contact sites","volume":"27","author":"Park","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1083\/jcb.201807019","article-title":"VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites","volume":"217","author":"Kumar","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1083\/jcb.201804111","article-title":"Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites","volume":"217","author":"Bean","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.43561","article-title":"Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility","volume":"8","author":"Yeshaw","year":"2019","journal-title":"eLife"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/hmg\/ddx054","article-title":"Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate","volume":"26","author":"Rzepnikowska","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1096\/fj.11-198317","article-title":"Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis","volume":"26","author":"Foller","year":"2012","journal-title":"FASEB J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1096\/fj.13-229286","article-title":"Chorein sensitivity of cytoskeletal organization and degranulation of platelets","volume":"27","author":"Schmidt","year":"2013","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1159\/000430363","article-title":"Chorein Sensitive Arrangement of Cytoskeletal Architecture","volume":"37","author":"Honisch","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1159\/000479901","article-title":"Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients","volume":"42","author":"Pelzl","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ceca.2018.05.001","article-title":"To die or not to die SGK1-sensitive ORAI\/STIM in cell survival","volume":"74","author":"Lang","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6457","DOI":"10.1038\/s41598-017-06451-1","article-title":"Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis","volume":"7","author":"Pelzl","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_18","first-page":"5652","article-title":"Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity","volume":"118","author":"Tomelleri","year":"2014","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1182\/blood-2016-07-727321","article-title":"A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis","volume":"128","author":"Lupo","year":"2016","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12027","DOI":"10.1523\/JNEUROSCI.0456-16.2016","article-title":"Neuronal dysfunction in iPSC-derived medium spiny neurons from chorea-acanthocytosis patients is reversed by Src kinase inhibition and F-actin stabilization","volume":"36","author":"Stanslowsky","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.mcn.2018.08.002","article-title":"Defective mitochondrial and lysosomal trafficking in chorea-acanthocytosis is independent of Src-kinase signaling","volume":"92","author":"Pal","year":"2018","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41467-017-02299-1","article-title":"Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation","volume":"9","author":"Naumann","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1146\/annurev.biochem.72.121801.161629","article-title":"Trk Receptors: Roles in Neuronal Signal Transduction","volume":"72","author":"Huang","year":"2003","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6298","DOI":"10.1523\/JNEUROSCI.2033-12.2013","article-title":"Mutant huntingtin alters retrograde transport of TrkB receptors in striatal dendrites","volume":"33","author":"Liot","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_25","first-page":"dmm036681","article-title":"VPS13A is closely associated with mitochondria and is required for efficient lysosomal degradation","volume":"12","author":"Vincent","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.nbd.2018.03.010","article-title":"Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation","volume":"115","author":"Kreiter","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Reinhardt, P., Glatza, M., Hemmer, K., Tsytsyura, Y., Thiel, C.S., Hoing, S., Moritz, S., Parga, J.A., Wagner, L., and Bruder, J.M. (2013). Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS ONE, 8.","DOI":"10.1371\/annotation\/6a917a2e-df4a-4ad9-99bb-6aa7218b833e"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep33694","article-title":"Ultra-sensitive detection of brain-derived neurotrophic factor (BDNF) in the brain of freely moving mice using an interdigitated microelectrode (IME) biosensor","volume":"6","author":"Yoo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.281.5381.1309","article-title":"Mitochondria and apoptosis","volume":"281","author":"Green","year":"1998","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.physiol.60.1.619","article-title":"The mitochondrial death\/ life regulator in apoptosis and necrosis","volume":"60","author":"Kroemer","year":"1998","journal-title":"Annu. Rev. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8238","DOI":"10.1523\/JNEUROSCI.1984-07.2007","article-title":"Mitochondrial and plasma membrane potential of cultured cerebellar neurons during glutamate-induced necrosis, apoptosis, and tolerance","volume":"27","author":"Ward","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1080\/15548627.2015.1034413","article-title":"TipC and the chorea-acanthocytosis protein VPS13A regulate autophagy in Dictyostelium and human HeLa cells","volume":"11","author":"Calvo","year":"2015","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"180241","DOI":"10.1038\/sdata.2018.241","article-title":"High content organelle trafficking enables disease state profiling as powerful tool for disease modelling","volume":"5","author":"Pal","year":"2018","journal-title":"Sci. Data"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0076-6879(07)28012-7","article-title":"Actin cytoskeleton architecture and signaling in osmosensing","volume":"428","author":"Papakonstanti","year":"2007","journal-title":"Methods Enzymol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1797\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:04:32Z","timestamp":1760173472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1797"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,5]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051797"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051797","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,5]]}}}