[TGF-β family signaling contributes to human cerebral small vessel disease].
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| 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.
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| Authors | Osamu Onodera |
| Journal | Rinsho shinkeigaku = Clinical neurology (Rinsho Shinkeigaku) Vol. 51 Issue 11 Pg. 943-4 (Nov 2011) ISSN: 1882-0654 [Electronic] Japan |
| PMID | 22277429 (Publication Type: Journal Article) |
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