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- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 5. |
- Nahar, Khayrun, et al.
(författare)
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Astrocyte-microglial association and matrix composition are common events in the natural history of primary familial brain calcification
- 2020
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 30:3, s. 446-64
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Tidskriftsartikel (refereegranskat)abstract
- Primary familial brain calcification (PFBC) is an age-dependent and rare neurodegenerative disorder characterized by microvascular calcium phosphate deposits in the 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) signaling, phosphate homeostasis or protein glycosylation-with unclear molecular links. To provide insight into the pathogenesis of PFBC, we analyzed murine models of PFBC for the first two of these processes in Pdgfb(ret/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 that calcified nodules in both of these models have a multilayered ultrastructure and occur in direct contact with reactive astrocytes and microglia. However, whereas nodules in Pdgfb(ret/ret) mice were large, solitary and smooth surfaced, the nodules in Slc20a2(-/-) mice were multi-lobulated and occurred in clusters. The regional distribution of nodules also differed between the two models. Proteomic analysis and immunofluorescence stainings revealed a common molecular composition of the nodules in the two models, involving proteins implicated in bone homeostasis, but also proteins not previously linked to tissue mineralization. While the brain vasculature of Pdgfb(ret/ret) mice has been reported to display reduced pericyte coverage and abnormal permeability, we found that Slc20a2(-/-) mice have a normal pericyte coverage and no overtly increased permeability. Thus, lack of pericytes and increase in permeability of the blood-brain barrier are likely not the causal triggers for PFBC pathogenesis. Instead, gene expression and spatial correlations suggest that astrocytes are intimately linked to the calcification process in PFBC.
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| 6. |
- O'Callaghan, Paul, et al.
(författare)
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Modeling the structural implications of an alternatively spliced Exoc3l2, a paralog of the tunneling nanotube-forming M-Sec
- 2018
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Ingår i: Plos One. - San Francisco, California, US : Public Library of Science (PLoS). - 1932-6203. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- The exocyst is a molecular tether that retains secretory vesicles at the plasma membrane prior to SNARE-mediated docking and fusion. However, individual exocyst complex components (EXOCs) may also function independently of exocyst assembly. Alternative splice variants of EXOC mRNA and paralogs of EXOC genes have been described and several have been attributed functions that may be independent of the exocyst complex. Here we describe a novel splice variant of murine Exoc3l2, which we term Exoc3l2a. We discuss possible functional implications of the resulting domain excision from this isoform of EXOC3L2 based on structural similarities with its paralog M-Sec (EXOC3L3), which is implicated in tunneling nanotube formation. The identification of this Exoc3l2 splice variant expands the potential for subunit diversity within the exocyst and for alternative functionality of this component independently of the exocyst.
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