Lumbago and alopecia in a patient with leukodystrophy: think on CARASIL

Souza, Paulo Victor Sgobbi de; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bullé

doi:10.1590/0004-282x20160076

Cited by 1 publication

(2 citation statements)

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“…The reported missense mutations were located in the protease active region of exons 3, 4, and 6 of HtrA1: 496C>T(R206C) (Souza et al. 2016 ), 616G>A(A206G) (Ibrahimi et al. 2017 ), 754G>A(A252T), 889G>A(V297M), 883G>A(G295A) (Mendioroz et al.…”

Section: Discussionmentioning

confidence: 99%

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HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

Wang

Wen

et al. 2022

Brain and Behavior

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Aims 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 (HtrA1L364P). Based on this previous study, we constructed a CARASIL mouse model (Mut‐hHtrA1L364P mouse, hereinafter referred to as Mut). This paper aimed to systematically study the behavior, pathology, and molecular biology of Mut mice and explore the pathogenesis and possible therapeutic strategies of CARASIL. Methods 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. Results 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. Conclusions 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.

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Section: Discussionmentioning

confidence: 99%

“…496C>T(R206C) (Souza et al 2016), 616G>A(A206G) (Ibrahimi et al 2017), 754G>A(A252T), 889G>A(V297M), 883G>A(G295A) (Mendioroz et al 2010), 1091T>C (L364P), 854C>T(P285L) (Chen et al 2013), and 821G>A(A274G) (Yu et al 2020). Although the diseasecausing genes have been well understood, the mechanism of the (Arima et al 2003).…”

Section: Discussionmentioning

confidence: 99%

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

Wang

Wen

et al. 2022

Brain and Behavior

View full text Add to dashboard Cite

show abstract

Lumbago and alopecia in a patient with leukodystrophy: think on CARASIL

Cited by 1 publication

References 2 publications

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

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