Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive movement disturbances caused by the selective loss of dopamine (DA) neurons in the substantia nigra. Despite the identification of the causal mechanisms underlying the pathogenesis of PD, effective treatments remain elusive. In this study, we observed that a low level of fetal bovine serum (FBS) effectively induced DA neurons in rat neural precursor cells (NPCs) by enhancing nuclear receptor-related 1 protein (NURR1) expression. Among the various components of FBS, the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were identified as key factors for the induction of DA neurons. Since an overdose of thyroid hormones can cause hyperthyroidism, we synthesized several thyroid hormone derivatives that can partially activate thyroid hormone receptors and induce the complete differentiation of NPCs into DA neurons. Two derivatives (#3 and #9) showed positive effects on the induction and maturation of DA neurons without showing significant affinity for the thyroid hormone receptor. They also effectively protected and restored DA neurons from neurotoxic insults. Taken together, these observations demonstrate that thyroid hormone derivatives can strongly induce DA neuron differentiation while avoiding excessive thyroid stimulation and might therefore be useful candidates for PD treatment.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of dopamine (DA) neurons in the substantia nigra (SN)[1,2]
Because the exogenous expression of nuclear receptor-related 1 protein (NURR1) can robustly increase the proportion of tyrosine hydroxylase (TH)+ neurons after in vitro differentiation, rat embryonic day 14 (E14) cortical neural precursor cells (NPCs) were transduced with a Nurr1-expressing retrovirus before differentiation
We investigated the effects of Fetal bovine serum (FBS) on DA neuron differentiation
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of dopamine (DA) neurons in the substantia nigra (SN)[1,2]. Www.nature.com/scientificreports neurons in rat and human NPCs. We found that only a small amount of the thyroid hormones in FBS were needed to drive DA neuron differentiation in cell cultures. To enable the use of thyroid hormones as a treatment for PD without inducing hyperthyroidism, we developed novel derivatives of thyroid hormones that have a low affinity for the thyroid hormone receptor but can increase the differentiation of DA neurons. These derivatives had protective effects on DA neurons after neurotoxic insult. We determined the relationship between thyroid hormones and DA neurons, and our observations may assist in the development of new medications for PD
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