＜シンポジウム09―2＞皮質下性血管障害の病態と治療
TGF-βファミリーシグナルの異常と脳小血管病
小野寺 理
新潟大学脳研究所生命科学リソース研究センター分子神経疾患資源解析学分野〔〒951―8122 新潟市中央区旭町1―757〕
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 ( hightemperature requirement A1). HTRA1 is a serine protease and inhibits TGF-β signaling in their protease activitydependent 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.
Full Text of this Article in Japanese PDF (170K)
(臨床神経, 51：943−944, 2011)
key words：TGF-β，CARASIL，HTRA1，脳小血管病
（受付日：2011年5月19日）
