The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited form of cerebral small vessel disease caused by mutations in conserved residues of NOTCH3. Affected arteries of CADASIL feature fibrosis and accumulation of NOTCH3. A variety of collagen subtypes (types I, III, IV, and VI) have been identified in fibrotic CADASIL vessels. Biglycan (BGN) and decorin (DCN), are Class I members of the small leucine-rich proteoglycan (SLRP) family that regulate collagen fibril size. Because DCN has been shown to deposit in arteries in cerebral small vessel disease, we tested whether BGN accumulates in arteries of CADASIL brains. BGN was strongly expressed in both small penetrating and leptomeningeal arteries of CADASIL brain. BGN protein was localized to all three layers of arteries (intima, media, and adventitia). Substantially more immunoreactivity was observed in CADASIL brains compared to controls. Immunoblotting of brain lysates showed a 4-fold increase in CADASIL brains (compared to controls). Messenger RNA encoding BGN was also increased in CADASIL and was localized by in situ hybridization to all three vascular layers in CADASIL. Human cerebrovascular smooth muscle cells exposed to purified NOTCH3 ectodomain upregulated BGN, DCN, and COL4A1 through mechanisms that are sensitive to rapamycin, a potent mTOR inhibitor. In addition, BGN protein interacted directly with NOTCH3 protein in cell culture and in direct protein interaction assays. In conclusion, BGN is a CADASIL-enriched protein that potentially accumulates in vessels by mTOR-mediated transcriptional activation and/or post-translational accumulation via protein interactions with NOTCH3 and collagen.

Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

“…Consistent with the tissue localization and function of NOTCH3, CADASIL mainly affects VSMCs in the tunica media. The specific pathological feature of CADASIL is the deposition of granular osmiophilic material (GOM) on the basement membrane of VSMCs, which is accompanied by prominent thickening of vessel walls due to the deposition of various extracellular matrix proteins (Tikka et al, 2009 ; Dong et al, 2012 ; Monet-Lepretre et al, 2013 ; Zhang et al, 2015b ; Capone et al, 2016 ). Abnormalities in proliferation ability, mitochondrial function and cytoskeleton structure have also been identified in VSMCs from CADASIL patients and mice (Domenga et al, 2004 ; Tikka et al, 2012 ; Viitanen et al, 2013 ; Panahi et al, 2018 ).…”

DNA Methylation Profiling Reveals the Change of Inflammation-Associated ZC3H12D in Leukoaraiosis

“…For example, BGN encodes a member of class I family of small leucine-rich proteoglycans (SLRPs), an extracellular matrix protein that plays roles in collagen assembly, regulation of inflammation and innate immune, maintainance of synapse stability by acting as a ligand of LRP6 and MuSK, interacting with TLR2/4 receptors, activation of Smad and Runx2 signaling, and modulation of TGF-β, and BMP2/4 functions (Wegrowski et al, 1995 ; Nastase et al, 2012 ). Recently, it was reported to be enriched in the brains of subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), indicating the potential roles in white matter changes (Zhang et al, 2015 ). This CADASIL-enriched protein can accumulate in vessels by mTOR-mediated transcriptional activation and/or post-translational accumulation which are mediated by the protein interactions with NOTCH3 and collagen (Zhang et al, 2015 ).…”

“…Recently, it was reported to be enriched in the brains of subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), indicating the potential roles in white matter changes (Zhang et al, 2015 ). This CADASIL-enriched protein can accumulate in vessels by mTOR-mediated transcriptional activation and/or post-translational accumulation which are mediated by the protein interactions with NOTCH3 and collagen (Zhang et al, 2015 ). DDR1 encodes a receptor tyrosine kinase which is ubiquitously expressed at low levels in a variety of epithelial tissues and with high levels of expression in the brain (Barbara Roig, 2010 ).…”

Expression of periaxin (PRX) specifically in the human cerebrovascular system: PDZ domain-mediated strengthening of endothelial barrier function

“…Localization of PRX in human brain was performed using a chromogenic detection method (Advanced Cell Diagnostics) 40 . Hybridization of antisense nucleic acid probes against PRX was followed by multiple non-enzymatic amplification steps, and, finally, probe detection was accomplished with an alkaline phosphatase conjugated terminal probe.…”