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Astrocyte – microglial association and matrix deposition define common pathogenic events in primary familial brain calcification
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. (Christer Betsholtz)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. (Christer Betsholtz)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Primary Familial Brain Calcification (PFBC) is an age-dependent and rare neurodegenerative disorder characterized by microvascular calcium phosphate deposits in deep brain regions. Known genetic causes of PFBC include loss-of-function mutations in genes involved in either of three processes - platelet-derived growth factor (PDGF) signalling, phosphate homeostasis or protein glycosylation - with unclear molecular links. To provide insight into the pathogenesis of PFBC, we analysed murine models of PFBC for two of these processes, Pdgfbret­­/ret and Slc20a2-/- mice, with regard to the structure, molecular composition, development and distribution of perivascular calcified nodules. Analyses by transmission electron microscopy and immunofluorescence revealed a multi-layered nodular ultrastructure and the direct contact between nodules and reactive astrocytes and microglia in both models. However, whereas Pdgfbret/ret mice developed large, solitary, smooth-surfaced nodules, Slc20a2-/- deposits were multi-lobulated and occurred in clusters. Nodular distribution in the brain also differed between the two mutants. Proteomic analysis and immunofluorescence revealed a common molecular composition of the nodules, involving proteins implicated in bone homeostasis, but also proteins not previously linked to tissue mineralization. Pericyte coverage and blood-brain barrier integrity were both intact in Slc20a2-/- mice, suggesting that these two features, both compromised in Pdgfbret/ret mice, are likely not the causal triggers of PFBC pathogenesis. Instead, gene expression and spatial correlations point to astrocytes as culprit cells in PFBC. 

National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-380085OAI: oai:DiVA.org:uu-380085DiVA, id: diva2:1298526
Available from: 2019-03-24 Created: 2019-03-24 Last updated: 2019-03-24
In thesis
1. The role of PDGF-B in brain blood vessels
Open this publication in new window or tab >>The role of PDGF-B in brain blood vessels
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of blood vessels is dependent on several molecular cues to form properly. A functional PDGF-B/PDGFR-b signaling is paramount for the investment of mural cells, that provide with support, to the developing vasculature. Mutations in PDGFB and PDGFRB are linked to PFBC, an age-dependent neurodegenerative condition manifested by vessel associated calcifications in the brain. The overall aim of the work presented in here was to investigate PFBC related calcifications and analyze the effects of impaired PDGF-B/PDGFR-b signaling on the formation of brain calcifications in different mouse models.

In paper I, we functionally analyzed PFBC-related PDGFB and PDGFRB mutations in vitro. While all PDGFB mutations lead to abolished protein function, PDGFRB mutations have more diverse consequences. We also show that reduced Pdgfb and Pdgfrb levels are insufficient for the formation of brain calcifications in several mouse strains. Moreover, region-specific susceptibility factors seem to reside in PFBC pathogenesis that are distinct from pericyte coverage and BBB deficiency.

In paper II, we described the molecular composition and cellular association of calcified nodules that develop in two mouse models of PFBC, Pdgfbret/ret and Slc20a2-/- mice. We show that the nodules are composed of pro- and anti-mineralization proteins and that they are in direct association with astrocytes and microglia

In paper III, we analyzed the effects of EC-specific ablation of PDGF-B in adult brain vasculature.  We report a substantial decrease of pericyte coverage and altered VSMC morphology and that this phenotype is inadequate to trigger the formation of calcifications or affect BBB integrity.

The aim of paper IV was to molecularly define the adult mouse brain vasculature by taking advantage of the scRNAseq technique. Here, we describe a gradual change in expression profile along the arteriovenous axis: ECs present a continuum along the axis while mural cell expression profile is punctuated. 

In summary, this thesis present detailed description of calcifications formed in mouse models of PFBC and address the role of impaired PDGF-B/PDGFR-b signaling for the formation of nodules in mice. Furthermore, the scRNaseq analysis performed on healthy adult brain vasculature has paved the way for future analysis in mouse models of PFBC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 48
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1556
Keywords
PFBC, PDGFB, PDGFRB, Brain vasculature, Mural cells
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-380088 (URN)978-91-513-0607-0 (ISBN)
Public defence
2019-05-15, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Supervisors
Available from: 2019-04-18 Created: 2019-03-24 Last updated: 2019-06-18

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