CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-β (TGF-β) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-β family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-β1 signaling triggered by proTGF-β1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum (ER), and cleaved proTGF-β1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-β1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-β1, specifically, the intracellular cleavage of proTGF-β1 in the ER.

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The expression of claudin-4 was investigated in human pancreas, pancreatic ductal adenocarcinomas, and intraductal papillary-mucinous tumors of the pancreas (IPMT), and compared with that of claudin-1. In human adult pancreatic specimens, both claudin-1 and claudin-4 were immunohistochemically found in main and branching pancreatic ducts, terminal ductules and acinic cells, with the exception of endocrine cells. Of 12 cases of pancreatic ductal adenocarcinoma, 11 (92%) had positive immunostaining for claudin-4, and seven (58%) for claudin-1. In 44 lesions of 22 cases of IPMT, including six hyperplastic foci distant from the main lesions, clauidin-1 was positive in three out of six (50%) hyperplastic foci, 14 out of 17 (82%) adenomas, three out of 10 (30%) borderline tumors, two out of six (33%) non-invasive carcinomas, and one out of five (20%) invasive carcinomas, producing a statistically negative correlation with histological tumor grades. In contrast, claudin-4 was negative in the six hyperplastic foci, and positive in four out of the 17 (24%) adenomas, five out of the 10 (50%) borderline tumors, five out of the six (83%) non-invasive carcinomas, and four out of the five (80%) invasive carcinomas, producing a statistically positive correlation with histological tumor grades. On study of IPMT subtypes, claudin-1 was positive in nine out of 10 (90%) clear-cell types, seven out of 20 (35%) dark-cell types, and four out of eight (50%) compact-cell types. In contrast, claudin-4 was positive in two out of the 10 (20%) clear-cell types, 13 out of the 20 (65%) dark-cell types, and three out of the eight (38%) compact-cell types. These distinct expression patterns of claudin-1 and claudin-4 suggest that both claudins serve as useful molecular markers for the tumor classification of IPMT.

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