title: [Molecular mechanism and therapeutic strategy for cerebral small vessel disease].
abstract: Hypertension is a well known risk factor for cerebral small vessel disease (SVD) characterized by MRI white matter hyperintensities called "leukoaraiosis". However, the molecular basis of SVD remains to be elucidated. Both twin and family studies have shown that leukoaraiosis is the most heritable cerebrovascular phenotype with a heritability estimated to be between 55% and 71%, suggesting genetic factors for SVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is hereditary SVD lacking hypertension. We have recently identified the causative gene, FHtrA1, for CARASIL by genome-wide linkage study and a candidate gene approach. HtrA1 is a serine protease that represses signaling by TGF-β family members. We found that mutated HtrA1 did not repress signaling by the TGF-β family members (BMP2, BMP4, and TGF-β1), resulting in vascular fibrosis with synthesis of extracellular matrix proteins. Our results indicate that disinhibition of TGF-β signaling underlies the molecular basis of CARASIL. Marfan's syndrome is an autosomal dominant connective tissue disorder caused by disinhibition of TGF-β signaling associated with FBN1 mutations. In a small cohort study, angiotensin II-receptor blockers (ARBs) therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilatation. This study provides a potential for developing a therapy targeting TGF-β signaling for SVD.
authors.affiliation: Department of Neurology, Akita Red Cross Hospital.
authors.forename: Kenju
authors.initials: K
authors.lastname: Hara
mesh_terms: D046589:CADASIL / Q000235:genetics / Q000628:therapy; D059345:Cerebral Small Vessel Diseases / Q000235:genetics* / Q000628:therapy*; D000071838:Fibrillin-1; D000071837:Fibrillins; D055106:Genome-Wide Association Study; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008382:Marfan Syndrome / Q000188:drug therapy / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D009154:Mutation; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D000074289:High-Temperature Requirement A Serine Peptidase 1; D008840:Microfilament Proteins; D012697:Serine Endopeptidases; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C474012:HTRA1 protein, human