臨床神経学

<シンポジウム(3)―14―2>小血管病の謎に迫る:CARASIL病態研究の最前線

CARASILの病態機序への考察

野崎 洋明

新潟大学医学部保健学科〔〒951―8518 新潟県新潟市中央区旭町通2番町746〕

Cerebral small-vessel disease, a common disorder in the aged, causes dementia and disability of motor function. The molecular pathology of the disorder remains to be elucidated. Missense and nonsense mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a hereditary cerebral small-vessel disease. HTRA1 represses transforming growth factor-β (TGF-β) signaling by its protease activity. CARASIL-associated mutant HTRA1s have decreased protease activity and fail to repress the TGF-β signaling, raising the possibility that chronic upregulation in the signaling pathways are involved in the pathogenesis of CARASIL. Here we show that increased expression of LAP and ED-A fibronectin are limited to affected small arteries in patients with CARASIL. We also demonstrate that HTRA1 cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum proceeding with processing by furin in trans Golgi network and reduces the amount of secreted TGF-β1 and CARASIL-associated mutant HTRA1s cannot. These results indicate that HtrA1 suppresses TGF-β signaling by aberrant processing of proTGF-β and the dysregulation of the signaling caused by mutated HTRA1s is involved in the pathogensis of CARASIL.
Full Text of this Article in Japanese PDF (245K)

(臨床神経, 52:1360−1362, 2012)
key words:遺伝性脳小血管病,TGF-βシグナル,HTRA1,ロサルタン,カンデサルタン

(受付日:2012年5月25日)