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

Sammanfattning: Synucleinopthies are neurodegenerative diseases characterised by the formation of α-synuclein-rich intracellular inclusions in neurons and glia. Traditionally, animalmodels and immortalized cell lines have been used to investigate why and how theseinclusions form, and how they impact on cellular function. Recent advances incellular reprogramming and directed differentiation have enabled the generation ofneurons and glia, providing new models to study alpha-synuclein biology in patienttailoredbrain cells.The work presented in this thesis aimed to establish a platform of novel models tofurther address questions relevant to α-synucleinopathies. We created a library ofhuman induced pluripotent stem cell lines from patients diagnosed with familialParkinson’s disease (PD) and multiple system atrophy (MSA), as well as healthycontrols, which we extensively characterized. Using these new cellular models, wegenerated defined regionalized cellular subtypes relevant for modelling PD and MSA,such as dopaminergic neurons, oligodendrocytes and astrocytes, using efficientdifferentiation protocols. In contrast to previous studies, we found that α-synuclein istransiently expressed in oligodendrocytes during development and in the adult humanbrain. We also devised a transgenic strategy for generating reporter lines, from whichpure populations of astrocytes could be obtained. These human astrocytes werecapable of releasing cytokines and chemokines in response to stressors, and readilytook up α-synuclein from their surroundings, demonstrating their relevance inmodelling of synucleinopathies. Braak’s hypothesis suggests that the pathology startsin the peripheral nervous system and progresses to the central nervous system (CNS),based on clinical observations of Lewy pathology distribution. We found thatfollowing injection into the intestinal wall of rats, α-synuclein was transported via thevagal nerve to the brain, thereby strengthening the hypothesis postulated by Braak.The models and cell systems presented in this thesis have provided unprecedentedpossibilities to address key questions relevant to the initiation and progression of α-synucleinopathies PD and MSA.