Htra1, or High temperature requirement A serine peptidase 1, is a serine protease. It modulates key signalling pathways like TGF-β, canonical WNT, and NOTCH, playing significant roles in cell proliferation, migration, fate determination, and protein aggregate control [2]. Mutations in Htra1 are associated with various disorders, making it a potential drug therapy target [2].

Homozygous Htra1 mutations cause Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), while heterozygous mutations can lead to cerebral small vessel disease (CSVD). Symptomatic carriers of heterozygous Htra1-related CSVD have a milder form of CARASIL, with later onset of neurological symptoms, fewer extraneurological findings, and less confluent white matter hyperintensities compared to CARASIL patients. The differing mutation locations in the two diseases suggest distinct molecular mechanisms in CSVD development [1,3]. In dilated cardiomyopathy, increased Htra1 expression is correlated with myocardial fibrosis. In vitro and in vivo experiments showed that suppressing Htra1 inhibited cardiac fibroblast-to-myofibroblast conversion, decreased type I collagen secretion, suppressed myocardial fibrosis, and improved left ventricular function [4].

In summary, Htra1 is crucial for modulating multiple signalling pathways and has diverse functions in cell biology. Its mutations are linked to neurodegenerative, cardiovascular, and other diseases. Research on Htra1, including through in vitro and in vivo experiments, provides insights into disease mechanisms and potential therapeutic targets for conditions like cerebral small vessel diseases and dilated cardiomyopathy-associated myocardial fibrosis [1,2,3,4].

References:

1. Uemura, Masahiro, Nozaki, Hiroaki, Kato, Taisuke, Mizuno, Toshiki, Onodera, Osamu. 2020. HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. In Frontiers in neurology, 11, 545. doi:10.3389/fneur.2020.00545. https://pubmed.ncbi.nlm.nih.gov/32719647/

2. Oka, Chio, Saleh, Razwa, Bessho, Yasumasa, Reza, Hasan Mahmud. 2021. Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases. In Saudi journal of biological sciences, 29, 1919-1927. doi:10.1016/j.sjbs.2021.11.056. https://pubmed.ncbi.nlm.nih.gov/35531175/

3. Zhou, Hui, Jiao, Bin, Ouyang, Ziyu, Shen, Lu, Fang, Liangjuan. 2022. Report of two pedigrees with heterozygous HTRA1 variants-related cerebral small vessel disease and literature review. In Molecular genetics & genomic medicine, 10, e2032. doi:10.1002/mgg3.2032. https://pubmed.ncbi.nlm.nih.gov/35946346/

4. Shi, Hongjie, Yuan, Ming, Cai, Jie, Zhou, Xianwu, Liu, Jinping. 2024. HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy. In Journal of translational medicine, 22, 297. doi:10.1186/s12967-024-05098-7. https://pubmed.ncbi.nlm.nih.gov/38515161/