Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most widely recognized monogenic form of small vessel disease (SVD), a common cause of stroke and dementia. By comprehensively understanding the molecular basis of CADASIL, we hope to identify molecular pathways which can be targeted to treat SVD. Most patients with CADASIL have mutations in NOTCH3, a gene expressed selectively in vascular smooth muscle. This has led to the hypothesis that CADASIL is caused by NOTCH3-induced impairment of protein clearance, cell separation, and smooth muscle cell death. Recently, mutations in the major basement membrane protein COL4A1 (vascular type IV collagen) have also been identified in familial SVD, suggesting that smooth muscle extracellular matrix abnormalities can also result in SVD. In this proposal, we hypothesize that NOTCH3 and COL4A form a functional unit that plays a central role in SVD. In preliminary studies, we show that 1) NOTCH3 and COL4A1 both accumulate and co-localize in blood vessels in CADASIL;2) NOTCH3 and COL4A1 form stable molecular complexes;3) NOTCH3 function is blocked by COL4A1;4) mutant NOTCH3 protein upregulates COL4A1 transcription. Consequently, we hypothesize that mutant NOTCH3 enhances COL4A1 accumulation, which blocks Notch regulation of smooth muscle genes and inhibits Notch clearance, leading to smooth muscle death.
Three aims will be pursued: (1) We will biochemically characterize interactions between NOTCH3 and COL4A. (2) We will test whether COL4A inhibits NOTCH function and clearance and promotes smooth muscle cell death. (3) We will examine NOTCH3 and COL4A in CADASIL mice and human cases of CADASIL to determine whether CADASIL is associated with genetic or epigenetic changes in the COL4A locus. By understanding the molecular underpinnings of CADASIL in detail, we hope to accrue knowledge essential for developing rational treatments for SVD.

Public Health Relevance

Small vessel disease (SVD) of the brain is a serious condition that results in stroke and vascular dementia and promotes Alzheimer's disease severity. The most common genetic cause of SVD is CADASIL. We have discovered that NOTCH3, the protein that is mutated in CADASIL, interacts with COL4A1, which is mutated in some patients with SVD. This raises the possibility the NOTCH3/COL4A complexes could be a common factor driving SVD. We will study the interaction between NOTCH3 and COL4A using molecular, cellular, and tissue analysis. Identifying this interaction could be an important step in designing strategies to slow down SVD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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Veterans Health Administration
Ann Arbor
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Gatti, John R; Zhang, Xiaojie; Korcari, Ejona et al. (2018) Redistribution of Mature Smooth Muscle Markers in Brain Arteries in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Transl Stroke Res :
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