CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) causes recurrent strokes and vascular dementia. The disease is caused most commonly by a single point mutation in the NOTCH3 gene, which leads to alteration in the number of cysteines. Abnormality in cysteine number may cause misfolding of the protein, leading to arterial smooth muscle dysfunction.
The lab is currently studying the mechanism of how mutant NOTCH3 leads to cellular injury. We are attempting to identify protein partners of NOTCH3. We are also actively pursuing the mechanisms of how the NOTCH3 gene is regulated, which may lead to ways to control NOTCH3 protein levels, which are typically elevated in CADASIL patients.
Antibodies have recently been developed against NOTCH3 proteins, and these antibodies react specifically with a conformation of NOTCH3 that is unique to CADASIL patients. We are currently characterizing the disease specific changes in NOTCH3 protein and attempting to understand how mutations in NOTCH3 lead to a conformational shift seen in patients.
Other studies involve the identification of proteins that accumulate with NOTCH3 in CADASIL blood vessels. More detailed investigations of these proteins ask: 1) why do these proteins accumulate in CADASIL arteries and 2) what are the consequences of build up of these proteins?