Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

Abstract

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

The Potential Impact of Neuroimaging and Translational Research on the Clinical Management of Lacunar Stroke

“…Lacunar infarcts are one of the distinctive markers of SVD, including both sporadic [16] and monogenic SVD types (such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [48][49][50]) and other rare hereditary diseases [51]. In histopathological studies of lacunar infarcts, the perforating arteries typically show thickening of the media, lipohyalinosis, segmental arterial disorganization, and fibrinoid degeneration [18].…”

Vertigo in Acute Stroke Is a Predictor of Brain Location but Is Not Related to Early Outcome: The Experience of Sagrat Cor Hospital of Barcelona Stroke Registry

“…The unusual association of lacunar stroke with vertigo could be due to the usual lesional topography of lacunar strokes in the centrum semiovale, internal capsule, basis pontis, and ventroposterolateral thalamic nucleus, which are all cerebral structures that are remote from the central vestibular connecting pathways [ 66 , 67 , 68 ].…”

Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

“…The molecular functions or biological processes of the proteins included ECM constituents, cytoskeleton, protein processing and vesicular traffic, and cell adhesion. 144 In a comparative postmortem proteome profiling analysis of two brain arteries in patients with the p.Arg1031Cys NOTCH3 mutation, Arboleda-Velasquez et al 114 identified 19 proteins whose levels differed significantly between patients with CADASIL and controls. Most of them were ECM proteins that were significantly increased in patients with CADASIL such as collagen 1α2, collagen12α1, collagen14α1, collagen18α1, laminin α5, laminin γ1, lactadherin, clusterin, vinculin, leucine-rich repeat proteoglycan, and perlecan.…”