RESUMEN
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.
RESUMEN
Iron is a trace element and a structural part of antioxidant enzymes, and its requirements vary according to age and gender. We hypothesized that iron deficiency (ID) leads to an increase in free radicals which mainly affect the brain, and the severity of damage would therefore be dependent on age and gender. Two groups of Wistar rats were evaluated evolutionarily: 100 rats (50 males; 50 females) with ID diet and 100 rats (50 males; 50 females) with standard diet. Both groups were offspring from mothers who were previously under the same dietary intervention. The ages studied roughly correspond to stages of human development: birth (0 postnatal day "PND" in rats), childhood (21 PND), early adolescence (42 PND), late adolescence (56 PND), and adulthood (70 PND). The following biomarkers in the brain, blood, and liver were analyzed: lipid peroxidation products (LPO), protein carbonyl content and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. It was demonstrated that ID subjects are born with high levels of LPO in the brain and low antioxidant activity, the damage being more severe in males. After birth, antioxidant defense focuses on the central level (brain) in ID females and on the peripheral level (blood and liver) in ID males. In two critical stages of development, birth and late adolescence, antioxidant protection is insufficient to counteract oxidative damage in ID subjects. Moreover, we observed that the variability of results in the literature on oxidative stress and ID comes from gender and age of the subjects under study. With this, we can establish patterns and exact moments to carry out studies or treatments (AU)
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