The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3
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ORIGINAL ARTICLE
The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3 Xiaojie Zhang & Soo Jung Lee & Marian F. Young & Michael M. Wang
Received: 9 October 2014 / Revised: 9 November 2014 / Accepted: 18 November 2014 # Springer Science+Business Media New York (Outside the USA) 2015
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 fourfold increase in CADASIL brains (compared to controls). Messenger RNA encoding BGN was also increased in CADASIL and was
X. Zhang : S. J. Lee : M. M. Wang (*) Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI 48109-5622, USA e-mail: [email protected] M. F. Young NIDCR, NIH, Bethesda, MD 20892, USA M. M. Wang Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-5622, USA M. M. Wang Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
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. Keywords CADASIL . Small leucine-rich proteoglycans . Biglycan . Collagen . Notch . Arteries . Protein interactions
Introduction Cerebral small vessel disease is a major cause of stroke and an important factor in the pathogenesis of dementia [1]. Genetic causes of cerebral small vessel disease provide opportunities to discover molecules which may participate in cerebral arteriopathy. The best-recognized inherited cause of small vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASI
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