Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson’s Disease Animal Model
Luis Daniel Bernal-Conde,
Verónica Peña-Martínez,
C. Alejandra Morato-Torres,
Rodrigo Ramos-Acevedo,
Óscar Arias-Carrión,
Francisco J. Padilla-Godínez,
Alexa Delgado-González,
Marcela Palomero-Rivero,
Omar Collazo-Navarrete,
Luis O. Soto-Rojas,
Margarita Gómez-Chavarín,
Birgitt Schüle,
Magdalena Guerra-Crespo
Affiliations
Luis Daniel Bernal-Conde
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Verónica Peña-Martínez
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
C. Alejandra Morato-Torres
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Rodrigo Ramos-Acevedo
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Óscar Arias-Carrión
Movement and Sleep Disorders Unit, Dr. Manuel Gea González General Hospital, Mexico City 14080, Mexico
Francisco J. Padilla-Godínez
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Alexa Delgado-González
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Marcela Palomero-Rivero
Neurodevelopment and Physiology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico
Omar Collazo-Navarrete
National Laboratory of Genomic Resources, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico
Luis O. Soto-Rojas
Laboratory of Molecular Pathogenesis, Laboratory 4, Building A4, Medical Surgeon Career, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, Mexico City 54090, Mexico
Margarita Gómez-Chavarín
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Birgitt Schüle
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA
Magdalena Guerra-Crespo
Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
Parkinson’s disease (PD) caused by SNCA gene triplication (3XSNCA) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3XSNCA and its absence is crucial. This study investigates the differentiation of human induced pluripotent stem cell (hiPSC)-derived floor-plate progenitors into dopaminergic neurons. Three different genotypes were evaluated in this study: patient-derived hiPSCs with 3XSNCA, a gene-edited isogenic line with a frame-shift mutation on all SNCA alleles (SNCA 4KO), and a normal wild-type control. Our aim was to assess how the substantia nigra pars compacta (SNpc) microenvironment, damaged by 6-hydroxydopamine (6-OHDA), influences tyrosine hydroxylase-positive (Th+) neuron differentiation in these genetic variations. This study confirms successful in vitro differentiation into neuronal lineage in all cell lines. However, the SNCA 4KO line showed unusual LIM homeobox transcription factor 1 alpha (Lmx1a) extranuclear distribution. Crucially, both 3XSNCA and SNCA 4KO lines had reduced Th+ neuron expression, despite initial successful neuronal differentiation after two months post-transplantation. This indicates that while the SNpc environment supports early neuronal survival, SNCA gene alterations—either amplification or knock-out—negatively impact Th+ dopaminergic neuron maturation. These findings highlight SNCA’s critical role in PD and underscore the value of hiPSC models in studying neurodegenerative diseases.
