Generating new models to study propagation and pathology of alpha-synuclein in Parkinson's disease and multiple system atrophy

Staffan Holmqvist

Research output: ThesisDoctoral Thesis (compilation)

680 Downloads (Pure)

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 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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Roybon, Laurent, Supervisor
  • Li, Jia-Yi, Supervisor
Award date2016 Sep 6
Place of PublicationLund
Publisher
ISBN (Print)978-91-7619-313-6
Publication statusPublished - 2016

Bibliographical note

Defence details
Date: 2016-09-06
Time: 13:00
Place: Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17, Lund
External reviewer(s)
Name: Kim, Kwang-Soo
Title: professor
Affiliation: Harvard Medical School
---
ISSN: 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:

Subject classification (UKÄ)

  • Neurosciences

Fingerprint

Dive into the research topics of 'Generating new models to study propagation and pathology of alpha-synuclein in Parkinson's disease and multiple system atrophy'. Together they form a unique fingerprint.

Cite this