Abstract
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 Lynkinase 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 treatin...Continue Reading
References
Dec 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·V A BankaitisS D Emr
Apr 29, 1998·Annual Review of Physiology·G KroemerM Resche-Rigon
Aug 28, 1998·Science·D R Green, J C Reed
Apr 5, 2003·Annual Review of Biochemistry·Eric J Huang, Louis F Reichardt
Aug 3, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Manus W WardJochen H M Prehn
Sep 19, 2007·Methods in Enzymology·Evangelia A Papakonstanti, Christos Stournaras
Jan 1, 2008·The Medico-legal Journal·Steve Walker
Apr 19, 2011·Handbook of Clinical Neurology·Ruth H WalkerAdrian Danek
Sep 29, 2011·Blood·Lucia De FranceschiGiel J C G M Bosman
Jan 10, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Michael FöllerFlorian Lang
Mar 24, 2012·Journal of Cell Science·Jae-Sook Park, Aaron M Neiman
Apr 10, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eva-Maria SchmidtFlorian Lang
Apr 12, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Géraldine LiotFrédéric Saudou
Jan 8, 2014·Acta Neuropathologica·Barbara S ConnollyAnthony E Lang
May 23, 2015·Autophagy·Sandra Muñoz-BracerasRicardo Escalante
Sep 1, 2015·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Sabina HonischChristos Stournaras
Jun 10, 2016·Molecular Biology of the Cell·Jae-Sook ParkAaron M Neiman
Sep 20, 2016·Scientific Reports·Yong Kyoung YooKyo Seon Hwang
Oct 21, 2016·Blood·Francesca LupoLucia De Franceschi
Nov 25, 2016·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nancy StanslowskyFlorian Wegner
Mar 24, 2017·Human Molecular Genetics·Weronika RzepnikowskaTeresa Zoladek
Jul 27, 2017·Scientific Reports·Lisann PelzlFlorian Lang
Aug 15, 2017·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Lisann PelzlFlorian Lang
Jan 25, 2018·Nature Communications·Marcel NaumannAndreas Hermann
Apr 10, 2018·Neurobiology of Disease·N KreiterA Hermann
May 29, 2018·Cell Calcium·Florian LangLudger Schöls
Jul 19, 2018·The Journal of Cell Biology·Björn D M BeanElizabeth Conibear
Aug 7, 2018·Molecular and Cellular Neurosciences·Hannes GlaßAndreas Hermann
Aug 11, 2018·The Journal of Cell Biology·Nikit KumarPietro De Camilli
Nov 14, 2018·Scientific Data·Arun PalAndreas Hermann
Feb 3, 2019·Disease Models & Mechanisms·Sandra Muñoz-BracerasRicardo Escalante
Feb 12, 2019·ELife·Wondwossen M YeshawOdy Cm Sibon