Conserved molecular features in cerebral small vessel disease

Small vessel disease (SVD) affects over 50% of Veterans over the age of 65 years. SVD increases the likelihood of dementia by 2-fold and of stroke by 3-fold. Severe inherited SVD results in permanent disability and dependency. We seek to understand the most common inherited cause of SVD: CADASIL, a disorder caused by dominantly acting mutations in NOTCH3. Hundreds of independent NOTCH3 mutations result in CADASIL, and virtually all involve cysteine residues. As such, most in the field believe that conformational alterations driven by aberrant disulfide bonding of NOTCH3 drives the disease process. In this proposal, we seek to answer a fundamental question about mutant NOTCH3 in CADASIL: Is there a signature alteration of the NOTCH3 protein shared by all CADASIL mutant proteins? The answer to this question affects the design of therapies. If there is a signature alteration of NOTCH3 caused by all CADASIL mutations, one therapy may be sufficient for all patients. However, if each mutation causes unique changes to the protein, multiple small molecule therapies will likely need to be devised. This has practical implications for planning of future clinical trials, since CADASIL is not a common condition. We will test if a range of mutants share conformational alterations, protein binding properties, and interactions with small molecules using reporter assays, proteome binding analysis, patient-based plasma proteomics, and chemical genomic screens. Successful completion of the aims will yield valuable deliverables: 1) data to support or refute that possibility that different CADASIL mutations share a common structural change; 2) identification of candidate plasma biomarkers for CADASIL; and 3) lead compounds that may be useful in treatment of SVD. Project Number: 1I01CX002783-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Michael Wang | Institution: VETERANS HEALTH ADMINISTRATION, ANN ARBOR, MI | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURD-E (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11051318