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Mapping of loci linked to degeneration of dopaminergic neurons in mice heterozygous for engrailed1

Brattås, Per Ludvik (2014) MOBN15 20132
Degree Projects in Molecular Biology
Abstract
Abstract

Engrailed1 (En1) is a developmental gene in the homeobox family, and it is well established as a key factor for programming and maintenance of dopaminergic neurons of the mesencephalon. Heterozygousity for the gene causes progressive degeneration of dopaminergic neurons of substantia nigra pars compacta and decreased striatal dopamine levels in most studied mouse strains, including Swiss mice. These phenotypes are also the hallmark of Parkinson’s disease pathology. However, C57Bl/6 mice do not suffer from degeneration of dopaminergic neurons when one En1 allele is deleted. This suggests that C57Bl/6 possess genetic variants that compensate for the lack of one En1 allele, presenting an opportunity to identify alleles causing... (More)
Abstract

Engrailed1 (En1) is a developmental gene in the homeobox family, and it is well established as a key factor for programming and maintenance of dopaminergic neurons of the mesencephalon. Heterozygousity for the gene causes progressive degeneration of dopaminergic neurons of substantia nigra pars compacta and decreased striatal dopamine levels in most studied mouse strains, including Swiss mice. These phenotypes are also the hallmark of Parkinson’s disease pathology. However, C57Bl/6 mice do not suffer from degeneration of dopaminergic neurons when one En1 allele is deleted. This suggests that C57Bl/6 possess genetic variants that compensate for the lack of one En1 allele, presenting an opportunity to identify alleles causing protection against degeneration of dopaminergic neurons. In order to map the potential neuroprotective loci in C57Bl/6, we intercrossed wild-type C57Bl/6 with SwissOF1-En1+/− to yield F2 mice for linkage analysis. Our data suggest that there are a large number of interacting QTL with small effect associated with dopaminergic cell survival. We found strongest evidence for three additive loci on chromosomes 2, 11 and 18, along with interactive loci on chromosomes 4, 6, 14 and 17. (Less)
Popular Abstract
Genes to protect us from Parkinson’s disease

Parkinson’s disease is one of the most common brain disorders, and is predicted to affect an increasing fraction of the world population in the future. Even though there are medications that that relieve the symptoms for a limited time, none can stop the disease from progressing. Using animal models, we have identified DNA variants that protect the cells that are lost in the disease. Understanding the mechanism behind this protection can aid the development of new therapies for Parkinons’s patients.

The main reason we don’t have a cure for Parkinson’s disease yet, is our incomplete understanding of why and how people develop the disease. We know that specific types of nerve cells that... (More)
Genes to protect us from Parkinson’s disease

Parkinson’s disease is one of the most common brain disorders, and is predicted to affect an increasing fraction of the world population in the future. Even though there are medications that that relieve the symptoms for a limited time, none can stop the disease from progressing. Using animal models, we have identified DNA variants that protect the cells that are lost in the disease. Understanding the mechanism behind this protection can aid the development of new therapies for Parkinons’s patients.

The main reason we don’t have a cure for Parkinson’s disease yet, is our incomplete understanding of why and how people develop the disease. We know that specific types of nerve cells that produce dopamine (a substance that transmit signals in the brain) are progressively lost. However, when the main symptoms emerge, half of these cells are already gone. A number of disease predisposing genes have in recent years been identified, and studies on these genes have helped researchers to better understand what happens in the disease.

From mice to men

One gene that is particularly important for healthy dopamine producing cells is called
Engrailed-1. This gene is turned on already before birth, to ensure healthy development of the brain, and is needed throughout life for survival of the cells. A deletion of the gene have been shown in many patients with Parkinson’s disease. In laboratory mice, the loss of the gene causes death of the same cells that are lost in patients. An interesting and rare case is a mouse strain called Black-6, which is able to survive and develop normally with only one of the two copies of the gene. This means that there must be something in the genes of Black-6 that protects the cells from dying.

To identify the protective gene(s), we compared the outcome of deletion of one copy of Engrailed-1 in second generation offsprings from crossing Black-6 with DNA of another mouse strain, Swiss, that lacks protection. We found 7 regions in the mouse genome that had an effect in protection and survival of the dopamine producing cells. One of these gene regions alone is not sufficient to save the dopamine producing cells, but a number of them are required together. However, it’s too early to say whether these genes will have a protective effect in humans, and we need to study these gene regions in detail to see how they actually save Black-6 from the cell loss. Ultimately, we hope to one day understand how we can treat and protect humans from Parkinson’s disease.

Advisor: Maria Swanberg
Master´s Degree Project in Cell and Molecular Biology, 45 credits
Master of Molecular Biology 2014
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Brattås, Per Ludvik
supervisor
organization
course
MOBN15 20132
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
4530294
date added to LUP
2014-07-03 11:10:10
date last changed
2014-07-03 11:10:10
@misc{4530294,
  abstract     = {{Abstract

Engrailed1 (En1) is a developmental gene in the homeobox family, and it is well established as a key factor for programming and maintenance of dopaminergic neurons of the mesencephalon. Heterozygousity for the gene causes progressive degeneration of dopaminergic neurons of substantia nigra pars compacta and decreased striatal dopamine levels in most studied mouse strains, including Swiss mice. These phenotypes are also the hallmark of Parkinson’s disease pathology. However, C57Bl/6 mice do not suffer from degeneration of dopaminergic neurons when one En1 allele is deleted. This suggests that C57Bl/6 possess genetic variants that compensate for the lack of one En1 allele, presenting an opportunity to identify alleles causing protection against degeneration of dopaminergic neurons. In order to map the potential neuroprotective loci in C57Bl/6, we intercrossed wild-type C57Bl/6 with SwissOF1-En1+/− to yield F2 mice for linkage analysis. Our data suggest that there are a large number of interacting QTL with small effect associated with dopaminergic cell survival. We found strongest evidence for three additive loci on chromosomes 2, 11 and 18, along with interactive loci on chromosomes 4, 6, 14 and 17.}},
  author       = {{Brattås, Per Ludvik}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Mapping of loci linked to degeneration of dopaminergic neurons in mice heterozygous for engrailed1}},
  year         = {{2014}},
}