transforming-growth-factor-beta and Cerebral-Arterial-Diseases

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life-threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high-temperature requirement serine protease gene mutation (HtrA1. Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF-β/Smad signaling pathway (TGF-β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real-time quantitative polymerase chain reaction (RT-PCR), and Western blot assay.. The food maze and water maze experiment data showed significant differences between the Mut and wild-type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees.. The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF-β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.

Topics: Alopecia; Animals; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Disorders; Cognitive Dysfunction; High-Temperature Requirement A Serine Peptidase 1; Leukoencephalopathies; Mice; RNA, Messenger; Signal Transduction; Spinal Diseases; Transforming Growth Factor beta

The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear.. In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL.. We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media.. 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.

Topics: Adult; Aged, 80 and over; Alopecia; Cerebral Arterial Diseases; Cerebral Arteries; Cerebral Infarction; Female; Genes, Recessive; High-Temperature Requirement A Serine Peptidase 1; Humans; Male; Middle Aged; Mutation; Pedigree; Serine Endopeptidases; Signal Transduction; Spondylosis; Syndrome; Transcription, Genetic; Transforming Growth Factor beta; Tunica Intima