Distinct neuroinflammatory pattern in multiple system atrophy
Year: 2021
Type: dissertation
Abstract: Multiple system atrophy (MSA) is a rare movement disorder characterized by a fast progressive and fatal disease course. Patients develop a variety of different symptoms including parkinsonism, cerebellar ataxia, and autonomic failure. Neuropathologically, these symptoms correlate with neurodegenerative processes related to oligodendrogliopathy predominantly observed in the striatonigral and olivopontocerebellar tract as well as autonomic nuclei. Due to the lack of biomarkers, a definite diagnosis of MSA is only possible by characteristic post-mortem features. Oligodendroglial alpha-synuclein positive cytoplasmic inclusions (GCIs) are the major neuropathological hallmark of MSA. A link between alpha-synuclein inclusions and impaired oligodendrocyte maturation has been discovered recently. However, the origin and formation of these oligodendroglial alpha-synuclein aggregates is currently highly debated. In addition, a severe neuroinflammation, including astro- and microgliosis, is described in post-mortem tissue of MSA patients. Yet, its initiation, dynamics, and contribution to disease progression is still elusive. Thus, the hypothesis of the present thesis is that oligodendroglial alpha-synucleinopathy is linked to a regionally specific and early immunological response in MSA. Furthermore, it is hypothesized that alpha-synuclein bearing oligodendrocytes express distinct factors mediating the observed neuroinflammatory response. Firstly, the regional-specific neuroinflammation was analyzed by immunohistochemical investigation of human post-mortem brain tissue of five MSA-P patients and five age- and gender-matched controls. An increased number of CD68 positive myeloid cells was observed in putaminal white matter regions. CD68 positive myeloid cells were located in close proximity to alpha-synuclein bearing oligodendrocytes, however, their numbers were independent of the overall alpha-synuclein load in this region. In contrast, astrogliosis was detected in the putaminal gray matter. Next, the neuroinflammatory response was analyzed using a transgenic MSA mouse model overexpressing human alpha-synuclein under the control of an oligodendrocyte-specific myelin basic protein (MBP) promoter. These mice express high levels of human alpha-synuclein in oligodendrocytes and present an early and severe motoric phenotype. Matching the results obtained from human post-mortem brain tissue, the number of myeloid cells was highly increased. In addition, activation and proliferation was observed in white matter brain regions (corpus callosum), whereas, astrocyte numbers and fiber density was increased in gray matter regions (motor cortex). Moreover, a high expression of pro-inflammatory cytokines such as Ccl2 and Cxcl10, which are important for chemotactic attraction and activation of myeloid cells, was detected in the white matter. Intriguingly, investigation of an early, pre-symptomatic disease stage (postnatal day 21, P21) indicates that the inflammatory processes are an early event in the disease course. Finally, it was investigated whether alpha-synuclein expressing oligodendrocytes are able to induce immunological responses. RNA sequencing analysis of primary rat oligodendrocytes overexpressing human alpha-synuclein identified increased expression of genes associated to immune effector processes, innate immune responses, cytokine production, and oxidative stress. As observed in murine white matter regions, particularly Cxcl10 and Ccl2 were upregulated in alpha-synuclein overexpressing oligodendrocytes. In conclusion, an early and regionally specific neuroinflammatory response was identified in human post-mortem brain tissue of MSA patients and its corresponding mouse model. The complementary activation of myeloid cells in the white and astrocytes in the gray matter indicates distinct cellular and regional underlying mechanisms. Moreover, a link between alpha-synuclein induced oligodendrogliopathy and myeloid cell responses was observed, suggesting a new concept of a pro-inflammatory function of oligodendrocytes. Interfering with this inflammatory crosstalk may provide a promising novel target for MSA therapy.
Author: Hoffmann, Alana
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7037524986