title: [TGF-β family signaling contributes to human cerebral small vessel disease].
abstract: The discovery of the causative gene for hereditary cerebral small vessel disease (CARASIL: Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) opens a new avenue for exploring the pathogenesis of cerebral small vessel disease. The causative gene for CARASIL is HTRA1 (high-temperature requirement A1). HTRA1 is a serine protease and inhibits TGF-β signaling in their protease activity-dependent manner. The CARASIL-associated mutant HTRA1s lost their protease activity and increase the TGF-β family signaling. However the precious molecular mechanism for inhibition of TGF-β signaling by HTRA1 has not been elucidated. We have found that HTRA1 aberrantly cleaved pro-TGF-β in an endoplasmic reticulum and the cleaved products were degraded by the endoplasmic reticulum-associated degradation pathway. The result reconfirms the importance of HTRA1 for TGF-β signaling. The study for Marfan syndrome, which is caused by the increasing TGF-β signaling in aortic artery, indicates that the angiotensin I receptor antagonist, a drug already in clinical use for hypertension, inhibits TGF-β signaling and ameliorates the disease progression in model mouse as well as patients with Marfan syndrome. In human brain, angiotensin I receptor antagonist also inhibits TGF-β signaling. Therefore angiotensin I receptor antagonist warrants investigation as a therapeutic strategy for patients with CARASIL.
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease, Niigata University.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000818:Animals; D059345:Cerebral Small Vessel Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D051379:Mice; D012697:Serine Endopeptidases / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases