title: Glial Dysfunction in Multiple System Atrophy
Creators: name: Battis, Kristina
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2025

description: Für meine Dissertation habe ich teilweise Daten aus meiner oben genannten Publikation wiederverwendet.
description: Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder with a fast progression and devastating disease course. Patients present a wide range of symptoms including autonomic failure, parkinsonism, and cerebellar ataxia. At present no disease modifying therapy is available. The major neuropathological hallmark of the disease is the accumulation of alpha-synuclein (α-syn) within oligodendroglial cytoplasmic inclusions (GCIs). Besides α-syn associated neurodegenerative processes, MSA is particularly linked to 1) a severe neuroinflammation, including microgliosis, as well as 2) profound demyelination. As the central nervous system (CNS)-resident macrophages and member of the myeloid cell lineage, microglia fulfill a variety of functions important for CNS development and homeostasis. Pathologically, the identification of distinct activation patterns including increased phagocytosis indicated a damaging role of myeloid cells in MSA. Thus, targeting inflammatory processes by altering myeloid cell responses may be a promising approach for MSA. Since the development of myeloid cells strongly depends on the colony stimulating factor 1 receptor (CSF1R) signaling pathway, small molecule inhibitors, such as PLX5622 have been used to deplete myeloid cells thereby potentially reducing neuroinflammation in the CNS. While CSF1R inhibition had several beneficial effects on the disease progression and severity of Alzheimer’s disease and multiple sclerosis, the effect of myeloid cell depletion in MSA is not known thus far. Therefore, PLX5622 was used to deplete myeloid cells in MBP29-hα-syn mice, a mouse model for MSA, to modify the disease progression as well as neuropathological processes. Interestingly, CSF1R inhibition revealed a two-faced outcome that improved the survival rate and delayed the onset of dystonic symptoms, whereas motor functions were severely impaired. Pathologically, there was no effect on α-syn or myelin levels as well as on OLIG2+ oligodendrocyte and GFAP+ astrocyte numbers upon PLX5622 administration. However, CSF1R inhibition reversed gene expression profiles related to myeloid cell activation and reduced gene expression associated with trans-synaptic signaling, signal release, and synapse pruning. While the observed transcriptional changes were accompanied by a loss of dopaminergic neurons in the substantia nigra pars compacta, an increased neuritic density within the striatum was revealed upon myeloid cell depletion in MBP29-hα-syn mice. Besides neuroinflammation, demyelination plays an important role in MSA. Myelin, formed by oligodendrocytes, is crucial for proper signal transduction, neuronal survival, and metabolic support. The severe myelin deficit present in MSA without a concurrent loss of oligodendrocytes led to the hypothesis that the transcriptional and metabolic profile of oligodendrocytes is changed driving the dysfunction of these cells in MSA. A human induced pluripotent stem cell (hiPSC) model was used to address this hypothesis. For this purpose, hiPSCs were derived from two healthy donors and oligodendroglial lineage specification was induced by the ectopic expression of the oligodendroglial transcription factors SOX10, OLIG2, and NKX6.2. Lentiviral particles were utilized to overexpress α syn within oligodendrocytes. Bulk RNA-sequencing analysis of hiPSC-derived oligodendrocytes revealed increased actin binding as well as a dysregulation of lipid associated genes upon α-syn overexpression. Furthermore, metabolic changes were identified by applying liquid chromatography-tandem mass spectrometry confirming alterations in lipid metabolism. Both, a fine-tuned actin remodeling and lipid metabolism are critical events during oligodendroglial differentiation and myelinogenesis. The precise exploration of structural and biochemical alterations may define a potential contributor to the myelin deficit in MSA. In conclusion, the biology of microglia and oligodendrocytes was analyzed in MSA. First, global myeloid cell depletion led to a mixed structural and functional outcome, pointing toward a more selective approach to redirect microglia response in MSA. Taken together, the link between intraoligodendroglial α-syn accumulation and demyelination due to lipid dysregulation may represent a novel potential implication in MSA-related pathogenesis.