Rinsho Shinkeigaku (Clinical Neurology)

Symposium 9

TGF-β family signaling contributes to human cerebral small vessel disease

Osamu Onodera, M.D., Ph.D.

Department of Molecular Neuroscience, Resource Branch for Brain Disease, Niigata University

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)

(CLINICA NEUROL, 51: 943|944, 2011)
key words: TGF-β, CARASIL, HTRA1, small vessel disease

(Received: 19-May-11)