Examining the effects of MLC1 mutations in induced astrocytes and on development of neuroglia using cerebral organoids
(2023) MOBN03 20212Degree Projects in Molecular Biology
- Abstract
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC), is a congenital leukodystrophy with childhood onset. It is an extremely rare genetic disorder of the brain that affects less than 1 per 1,000,000 live births. Patients typically present macrocephaly during early childhood and later develop symptoms like decreased motor and cognitive functions, and epileptic seizures, all of which usually result in reduced life expectancy of the child. The pathology of MLC is characterized by white matter edema, vacuolization of myelin sheets and astrocyte endfeets and defects in crucial astrocytic functions such as ion/fluid homeostasis. The main cause of MLC in the majority of patients has been identified to be mutations in MLC1 and... (More)
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC), is a congenital leukodystrophy with childhood onset. It is an extremely rare genetic disorder of the brain that affects less than 1 per 1,000,000 live births. Patients typically present macrocephaly during early childhood and later develop symptoms like decreased motor and cognitive functions, and epileptic seizures, all of which usually result in reduced life expectancy of the child. The pathology of MLC is characterized by white matter edema, vacuolization of myelin sheets and astrocyte endfeets and defects in crucial astrocytic functions such as ion/fluid homeostasis. The main cause of MLC in the majority of patients has been identified to be mutations in MLC1 and HepaCAM, encoding two proteins that are significantly expressed in astrocytes and play critical roles in their physiology. Most studies done on the disease to date have not been able to adequately recapitulate the disease phenotypes observed in patients and the complete mechanism of the pathogenesis still remains largely unknown. In this study, we used two MLC mutant hESC lines to demonstrate their ability to produce astrocytes and cerebral organoids. These were then characterized to be used as viable MLC disease models, potentially better representing disease progression in humans. Interestingly, we found that one of the mutants had heightened levels of MBP, contrary to the negative effect on myelination documented in a few other studies. Both mutants also showed an enrichment of GFAP. (Less)
- Popular Abstract
- Investigating the effects of MLC1 mutations using new stem cell-based disease models
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a extremely rare genetic brain disease with childhood onset which currently has no effective treatment. Due to the vast number of highly complex molecular interactions of the brain that remain largely unknown even today, understanding the disease and developing medicines has been a challenge. With the help of stem cell technology, we are able to create new and improved disease models like never before, which can lend valuable information on the disease.
MLC is a brain disease, belonging to a class of ailments termed as leukodystrophies; diseases that affect the white matter in the... (More) - Investigating the effects of MLC1 mutations using new stem cell-based disease models
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a extremely rare genetic brain disease with childhood onset which currently has no effective treatment. Due to the vast number of highly complex molecular interactions of the brain that remain largely unknown even today, understanding the disease and developing medicines has been a challenge. With the help of stem cell technology, we are able to create new and improved disease models like never before, which can lend valuable information on the disease.
MLC is a brain disease, belonging to a class of ailments termed as leukodystrophies; diseases that affect the white matter in the brain. MLC has been identified to be caused by genetic mutations in two genes i.e., MLC1 and HepaCAM, highly expressed in astrocytes, which are star shaped brain cells. These mutations cause disruption in the normal functioning of astrocytes, which affects many important brain functions. The effects of MLC disease start at birth, meaning children born with MLC mutations suffer from symptoms like swelling of the head, decreased motor and cognitive functions, epileptic seizures, and generally a reduced life expectancy. Currently there exists no cure for the disease and treatment is limited to symptomatic treatment and lifestyle changes.
Modern science has made tremendous strides in the field of disease modelling of neurological disorders since the discovery of stem cells. Pluripotent stem cells have the ability to convert into any cell type of the body, a property that can be exploited to produce different cells of interest, for example brain cells, in order to study them and understand their function and properties. In combination with genetic engineering tools like CRISPR/Cas, we can make certain changes to the genetic information in the stem cells such as introducing mutations in genes of interest before converting them to the cells of desired lineages.
In this study, we have used novel strategies to study the effect of MLC1 mutations in astrocytes and associated cells of the brain with the help of stem cell-based disease models of MLC. Embryonic stem cells with and without MLC1 mutations were used to produce astrocytes and brain organoids i.e., self-organizing three-dimensional tissues consisting of brain specific cell types that mimics structure and function of the human brain. These were analyzed for differences in MLC disease related proteins. Our results showed surprising distinctions in some of these disease related proteins between the normal and mutant cells.
Our work on astrocytes and organoids demonstrates that they can be valuable MLC disease models, which can help reach new insights into the development and progression of the disease allowing for future research to explain the disease mechanisms in humans and perhaps, develop medical treatments for MLC in the future.
Master´s project in Molecular Biology, 60 credits, MOBN03, Department of Biology,
Lund University
Supervisors: Ella Quist, Henrik Ahlenius
Stem Cells, Aging and Neurodegeneration, Department of Clinical Sciences, Neurology, Lund Stem Cell Center, Lund University, Sweden (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9140732
- author
- Paul, Francis
- supervisor
-
- Ella Quist LU
- Henrik Ahlenius LU
- organization
- course
- MOBN03 20212
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9140732
- date added to LUP
- 2023-11-01 14:20:38
- date last changed
- 2023-11-01 14:20:38
@misc{9140732,
abstract = {{Megalencephalic leukoencephalopathy with subcortical cysts (MLC), is a congenital leukodystrophy with childhood onset. It is an extremely rare genetic disorder of the brain that affects less than 1 per 1,000,000 live births. Patients typically present macrocephaly during early childhood and later develop symptoms like decreased motor and cognitive functions, and epileptic seizures, all of which usually result in reduced life expectancy of the child. The pathology of MLC is characterized by white matter edema, vacuolization of myelin sheets and astrocyte endfeets and defects in crucial astrocytic functions such as ion/fluid homeostasis. The main cause of MLC in the majority of patients has been identified to be mutations in MLC1 and HepaCAM, encoding two proteins that are significantly expressed in astrocytes and play critical roles in their physiology. Most studies done on the disease to date have not been able to adequately recapitulate the disease phenotypes observed in patients and the complete mechanism of the pathogenesis still remains largely unknown. In this study, we used two MLC mutant hESC lines to demonstrate their ability to produce astrocytes and cerebral organoids. These were then characterized to be used as viable MLC disease models, potentially better representing disease progression in humans. Interestingly, we found that one of the mutants had heightened levels of MBP, contrary to the negative effect on myelination documented in a few other studies. Both mutants also showed an enrichment of GFAP.}},
author = {{Paul, Francis}},
language = {{eng}},
note = {{Student Paper}},
title = {{Examining the effects of MLC1 mutations in induced astrocytes and on development of neuroglia using cerebral organoids}},
year = {{2023}},
}