Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson's Disease Animal Model.

Autor: Bernal-Conde LD; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Peña-Martínez V; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Morato-Torres CA; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA., Ramos-Acevedo R; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Arias-Carrión Ó; Movement and Sleep Disorders Unit, Dr. Manuel Gea González General Hospital, Mexico City 14080, Mexico., Padilla-Godínez FJ; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Delgado-González A; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Palomero-Rivero M; Neurodevelopment and Physiology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico., Collazo-Navarrete O; National Laboratory of Genomic Resources, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico., Soto-Rojas LO; 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., Gómez-Chavarín M; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico., Schüle B; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA., Guerra-Crespo M; Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.; Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico.
Jazyk: angličtina
Zdroj: Life (Basel, Switzerland) [Life (Basel)] 2024 Jun 05; Vol. 14 (6). Date of Electronic Publication: 2024 Jun 05.
DOI: 10.3390/life14060728
Abstrakt: Parkinson's disease (PD) caused by SNCA gene triplication (3X SNCA ) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3X SNCA 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 3X SNCA , 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 3X SNCA 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.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje