Morphologische Charakterisierung der Alpha-Synukleinopathie in einem Parkinson-Mausmodell
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Philipps-Universität Marburg
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Abstract
Parkinson's disease is a neurodegenerative disease characterized by motor and nonmotor
symptoms. It appears to be caused by a complex interplay of genetic and
environmental factors that influence numerous fundamental cellular processes. The
histopathological correlate of the disease are cytoplasmic aggregates, which consist
mainly of misfolded a-synuclein and are called Lewy bodies or Lewy neurites, depending
on their localization. Suitable in vivo models are essential for a more precise
understanding of the underlying mechanism and ultimately for the establishment of
new, disease-modifying therapeutic options. One such model is the intracerebral
injection of preformed a-synuclein fibrils into mice. The aim of this study was to
establish and phenotype the model based on the injection of preformed fibrils in our
research group and to use the model to carry out studies that should contribute to a
better understanding of induced a-synuclein pathology at the cellular level. For this
purpose, preformed fibrils of murine a-synuclein were injected into the substantia nigra
pars compacta of mice and sacrificed 12 weeks later. The mouse cohort for the
examination via transmission electron microscopy also received a fluorogold injection
into the striatum. The brains of the mice were then dissected, prepared and cut. The
production of these brain slices, including injection, surgery and preparation of the brain
slices are explicitly not part of this doctoral project. The brain sections provided were
then stained as part of this doctoral project and analyzed using immunohistochemistry
or transmission electron microscopy.
Specifically, this work covered three topics. Firstly, it was investigated whether the
preformed a-synuclein fibrils trigger an aggregate pathology after intracerebral
injection into the substantia nigra pars compacta and whether this is accompanied by
measurable neurodegeneration. In addition, the spread of the pathology to other brain regions was evaluated using a scoring system and compared with the substantia nigra
pars compacta connectome and the Braak stages. Finally, the aggregate pathology was
examined and characterized using electron microscopy.
The above studies showed that injection of preformed a-synuclein fibrils induced a
pronounced aggregate pathology with a transduction rate of about 40%, which was
accompanied by a cell loss of about 30%. The aggregates were immunoreactive for S129-
phosphorylated a-synuclein and p62 and resistant to proteinase K degradation. Thus, they exhibited important characteristics of human Lewy bodies. Furthermore, the pathology spread over long distances to almost all brain regions examined. The spread occurred predominantly on the ipsilateral side and rostrally. The pattern of spread could not be explained solely by the connectome of the substantia nigra pars compacta. Instead, an interplay of a-synuclein-specific factors and the characteristic properties of transmitting and receiving cells could determine the spreading pattern. In agreement with studies on human Lewy bodies, electron microscopic characterization revealed a complex perinuclear aggregate pathology with a high proportion of dysmorphic and degenerated mitochondria as well as a large number of lysosomes in different states of activation and a large number of tubulo-vesicular structures. Accordingly, the aggregate pathology shows the image of a lipidopathy rather than a proteinopathy under the electron microscope. Thus, in this study, the model based on the injection of preformed a-synuclein fibrils was successfully established in our group and it was shown that the induced aggregate pathology reproduces the most important features of human Lewy bodies. Furthermore, the results of this study reveal various aspects of disease progression and thus provide a valuable basis for further investigation of the underlying mechanisms of proliferation and cellular processes involved.
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Dates
Created: 2024Issued: 2025-02-12Updated: 2025-02-12
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
DFG-subjects
MausmodellNeurologieMorbus ParkinsonProteinopathieParkinson-KrankheitAlpha-SynukleinopathieParkinson's DiseaseElektronenmikroskopie
DDC-Numbers
610
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Grotmann, Constantin Alexander: Morphologische Charakterisierung der Alpha-Synukleinopathie in einem Parkinson-Mausmodell. : Philipps-Universität Marburg 2025-02-12. DOI: https://doi.org/10.17192/z2025.0037.