Mitochondrial Instability, Lack of Erk1/2 Activation and High Expression of P75NTR in Engrailed-Deficient Mesencephalic Dopaminergic Neurons
type: CreativeWork
description: Progressive loss of mesencephalic dopaminergic (mesDA) neurons is the main pathological feature of Prakinson’s Disease. The homeobox transcription factors, Engrailed-1 and Engrailed-2, are essential for survival and long-term maintenance of this neuronal population. In mutant embryos, null for both genes, the mesDA neurons are generated and start to express their neurotransmitter phenotype, but fail to differentiate and die during midgestation. The mice, heterozygous for Engrailed-1 and homozygous null for Engrailed-2, suffer a Parkinson’s Disease-like postnatal degeneration of their nigral DA neurons. Prior studies had shown that the Engrailed-deficient mesDA neurons die by apoptosis, evident from activation of caspase-3 and presence of pyknotic nuclei. The subject of this study was to elaborate more on the molecular pathway of death and to find out the mechanisms of survival by interfering with this process. In this work, I demonstrate that reduction in expression of Engrailed in mesDA neurons results in a higher sensitivity to mitochondrial apoptotic insult. The increased vulnerability to treatment with MPTP or specific inhibitors of Bcl-2 and Bcl-XL causes release of cytochrome C from the mitochondrial inter-membrane space into the cytosol and subsequent activation of caspases. I also show that the Engrailed deficiency results in increased expression of P75 neurotrophin receptor, which is causal to death of the neurons. The death of Engrailed double mutant mesDA neurons, as a direct result of high expression of P75, can be inhibited by application of TrkB/C-specific neurotrophins, BDNF, NT4 or NT3, by siRNA knockdown (of P75) or by addition of an inhibiting antibody for P75. The rescue effect of these survival factors is diminished by concurrent treatment of the primary cell cultures with an inhibitor of the extracellular signal regulated kinase1/2 (Erk1/2) pathway. Additionally, there is an inverse correlation between expression of P75 and phosphorylation of Er…
abstract: Progressive loss of mesencephalic dopaminergic (mesDA) neurons is the main pathological feature of Prakinson’s Disease. The homeobox transcription factors, Engrailed-1 and Engrailed-2, are essential for survival and long-term maintenance of this neuronal population. In mutant embryos, null for both genes, the mesDA neurons are generated and start to express their neurotransmitter phenotype, but fail to differentiate and die during midgestation. The mice, heterozygous for Engrailed-1 and homozygous null for Engrailed-2, suffer a Parkinson’s Disease-like postnatal degeneration of their nigral DA neurons. Prior studies had shown that the Engrailed-deficient mesDA neurons die by apoptosis, evident from activation of caspase-3 and presence of pyknotic nuclei. The subject of this study was to elaborate more on the molecular pathway of death and to find out the mechanisms of survival by interfering with this process. In this work, I demonstrate that reduction in expression of Engrailed in mesDA neurons results in a higher sensitivity to mitochondrial apoptotic insult. The increased vulnerability to treatment with MPTP or specific inhibitors of Bcl-2 and Bcl-XL causes release of cytochrome C from the mitochondrial inter-membrane space into the cytosol and subsequent activation of caspases. I also show that the Engrailed deficiency results in increased expression of P75 neurotrophin receptor, which is causal to death of the neurons. The death of Engrailed double mutant mesDA neurons, as a direct result of high expression of P75, can be inhibited by application of TrkB/C-specific neurotrophins, BDNF, NT4 or NT3, by siRNA knockdown (of P75) or by addition of an inhibiting antibody for P75. The rescue effect of these survival factors is diminished by concurrent treatment of the primary cell cultures with an inhibitor of the extracellular signal regulated kinase1/2 (Erk1/2) pathway. Additionally, there is an inverse correlation between expression of P75 and phosphorylation of Er…
author: Alavian, Kambiz Nassirpour
date published: 2006-11-09
date modified: 2026-07-24T02:30:34Z
provider: Universität Heidelberg
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Universität Heidelberg