Generating new models to study propagation and pathology of alpha-synuclein in Parkinson's disease and multiple system atrophy
(2016)- Abstract
- Synucleinopthies are neurodegenerative diseases characterised by the formation of α-
synuclein-rich intracellular inclusions in neurons and glia. Traditionally, animal
models and immortalized cell lines have been used to investigate why and how these
inclusions form, and how they impact on cellular function. Recent advances in
cellular reprogramming and directed differentiation have enabled the generation of
neurons and glia, providing new models to study alpha-synuclein biology in patienttailored
brain cells.
The work presented in this thesis aimed to establish a platform of novel models to
further address questions relevant to α-synucleinopathies. We created a library of
human induced pluripotent stem... (More) - Synucleinopthies are neurodegenerative diseases characterised by the formation of α-
synuclein-rich intracellular inclusions in neurons and glia. Traditionally, animal
models and immortalized cell lines have been used to investigate why and how these
inclusions form, and how they impact on cellular function. Recent advances in
cellular reprogramming and directed differentiation have enabled the generation of
neurons and glia, providing new models to study alpha-synuclein biology in patienttailored
brain cells.
The work presented in this thesis aimed to establish a platform of novel models to
further address questions relevant to α-synucleinopathies. We created a library of
human induced pluripotent stem cell lines from patients diagnosed with familial
Parkinson’s disease (PD) and multiple system atrophy (MSA), as well as healthy
controls, which we extensively characterized. Using these new cellular models, we
generated defined regionalized cellular subtypes relevant for modelling PD and MSA,
such as dopaminergic neurons, oligodendrocytes and astrocytes, using efficient
differentiation protocols. In contrast to previous studies, we found that α-synuclein is
transiently expressed in oligodendrocytes during development and in the adult human
brain. We also devised a transgenic strategy for generating reporter lines, from which
pure populations of astrocytes could be obtained. These human astrocytes were
capable of releasing cytokines and chemokines in response to stressors, and readily
took up α-synuclein from their surroundings, demonstrating their relevance in
modelling of synucleinopathies. Braak’s hypothesis suggests that the pathology starts
in the peripheral nervous system and progresses to the central nervous system (CNS),
based on clinical observations of Lewy pathology distribution. We found that
following injection into the intestinal wall of rats, α-synuclein was transported via the
vagal nerve to the brain, thereby strengthening the hypothesis postulated by Braak.
The models and cell systems presented in this thesis have provided unprecedented
possibilities to address key questions relevant to the initiation and progression of α-
synucleinopathies PD and MSA. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/faf6583f-e694-45bd-bf1a-0faef8001729
- author
- Holmqvist, Staffan LU
- supervisor
-
- Laurent Roybon LU
- Jia-Yi Li LU
- opponent
-
- professor Kim, Kwang-Soo, Harvard Medical School
- organization
- publishing date
- 2016
- type
- Thesis
- publication status
- published
- subject
- pages
- 94 pages
- publisher
- Lund University: Faculty of Medicine
- defense location
- Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17, Lund
- defense date
- 2016-09-06 13:00:00
- ISBN
- 978-91-7619-313-6
- language
- English
- LU publication?
- yes
- additional info
- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:
- id
- faf6583f-e694-45bd-bf1a-0faef8001729
- date added to LUP
- 2016-08-15 16:47:34
- date last changed
- 2019-11-19 13:49:11
@phdthesis{faf6583f-e694-45bd-bf1a-0faef8001729,
abstract = {{Synucleinopthies are neurodegenerative diseases characterised by the formation of α-<br/>synuclein-rich intracellular inclusions in neurons and glia. Traditionally, animal<br/>models and immortalized cell lines have been used to investigate why and how these<br/>inclusions form, and how they impact on cellular function. Recent advances in<br/>cellular reprogramming and directed differentiation have enabled the generation of<br/>neurons and glia, providing new models to study alpha-synuclein biology in patienttailored<br/>brain cells.<br/>The work presented in this thesis aimed to establish a platform of novel models to<br/>further address questions relevant to α-synucleinopathies. We created a library of<br/>human induced pluripotent stem cell lines from patients diagnosed with familial<br/>Parkinson’s disease (PD) and multiple system atrophy (MSA), as well as healthy<br/>controls, which we extensively characterized. Using these new cellular models, we<br/>generated defined regionalized cellular subtypes relevant for modelling PD and MSA,<br/>such as dopaminergic neurons, oligodendrocytes and astrocytes, using efficient<br/>differentiation protocols. In contrast to previous studies, we found that α-synuclein is<br/>transiently expressed in oligodendrocytes during development and in the adult human<br/>brain. We also devised a transgenic strategy for generating reporter lines, from which<br/>pure populations of astrocytes could be obtained. These human astrocytes were<br/>capable of releasing cytokines and chemokines in response to stressors, and readily<br/>took up α-synuclein from their surroundings, demonstrating their relevance in<br/>modelling of synucleinopathies. Braak’s hypothesis suggests that the pathology starts<br/>in the peripheral nervous system and progresses to the central nervous system (CNS),<br/>based on clinical observations of Lewy pathology distribution. We found that<br/>following injection into the intestinal wall of rats, α-synuclein was transported via the<br/>vagal nerve to the brain, thereby strengthening the hypothesis postulated by Braak.<br/>The models and cell systems presented in this thesis have provided unprecedented<br/>possibilities to address key questions relevant to the initiation and progression of α-<br/>synucleinopathies PD and MSA.}},
author = {{Holmqvist, Staffan}},
isbn = {{978-91-7619-313-6}},
language = {{eng}},
publisher = {{Lund University: Faculty of Medicine}},
school = {{Lund University}},
title = {{Generating new models to study propagation and pathology of alpha-synuclein in Parkinson's disease and multiple system atrophy}},
url = {{https://lup.lub.lu.se/search/files/10951388/E_spik_staffan_G5.pdf}},
year = {{2016}},
}