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Staffan thesis cover


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.


Page Manager:
Laurent Roybon, PhD, Docent
Stem Cell Laboratory for CNS Disease Modeling
Department of Experimental Medical Science
Lund University
Sölvegatan 19
SE-221 84 Lund, Sweden

Tel: +46 46 222 9833