臨床神経学

第51回日本神経学会総会

<シンポジウム03―2>神経難病の克服―単一遺伝子病からのアプローチ―
脳小血管病の分子病態と治療の展望

原 賢寿

秋田赤十字病院神経内科〔〒010―1495 秋田市上北手猿田字苗代沢222―1〕
新潟大学脳研究所神経内科〔〒951―8585 新潟市中央区旭町通1―757〕

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.
Full Text of this Article in Japanese PDF (337K)

(臨床神経, 50:852−854, 2010)
key words:脳小血管病,CARASIL,HtrA1,TGF-βシグナル伝達,Marfan症候群

(受付日:2010年5月21日)