Finding the cause of Moyamoya disease worsening, which causes blood vessels in the brain to bloom like a haze

Moyamoya disease is a disease in which certain blood vessels in the brain (the end of the internal carotid artery) that supply blood to the brain are narrowed or blocked. To compensate for insufficient blood flow, replacement blood vessels develop from the external carotid artery, and these vessels are abnormally thin.

A domestic research team presented research results showing that one of the causes of worsening moyamoya disease is the decline in the autophagy ability of vascular endothelial cells that interact with the RNF213 mutant gene.

The research team led by Hong Ji-man, professor of neurology at Ajou University Hospital (researcher Shin Hee-sun), confirmed that in patients with moyamoya disease with the RNF213 gene mutation, the disease progresses more seriously when exposed to stressful environments such as nutritional deficiency (starvation) and hypoxia.

The research team compared 30 patients with moyamoya disease and 15 normal people. The patient group was divided into the RNF213 gene normal group (15 patients) and the mutant group (15 patients), and autophagy ability was analyzed in peripheral blood mononuclear cells.

As a result, endothelial cell function in patients with the genetic modification was impaired, and autophagy was abnormally suppressed in the genetically modified cells.

In addition, the normal and mutant RNF213 genes were randomly overexpressed in human umbilical vein endothelial cells, and then the cells were exposed to hypoxia and glucose deprivation for 2 hours to resemble the intracranial environment of a patient with moyamoya disease.

As a result, more autophagic cysts were observed in endothelial cells of RNF213 gene mutation. Autophagy cysts are a form observed when abnormal proteins are removed from the cytoplasm of our body.

In particular, after exposure to hypoxia and glucose deficiency, autophagy inhibition and vascular endothelial cell function decline were clearly observed, and more intracellular autophagic cysts were observed through transmission electron microscopy.

The research team confirmed that the genetically modified cells recovered normal autophagy function after using an autophagy inducer.

The RNF213 protein is known to play an important role in removing unnecessary or abnormal proteins from our body, and is a physiological mechanism that maintains cell homeostasis even under cellular stress conditions through autophagy or removal of unnecessary proteins.

The research team said, “It is presumed that inhibition of autophagy and decline in vascular endothelial cell function worsens moyamoya disease by causing accumulation of abnormal proteins in cerebral blood vessels and decreased cerebral blood flow.”

Professor Hong Ji-man said, “This study is significant in that it is the first to confirm that environmental stress, such as hypoxia, seriously progresses the disease in RNF213 gene mutation moyamoya disease.”

Researcher Shin Hee-seon, the first author, said, “We are looking forward to the development and clinical application of new drugs by identifying the relationship between autophagy and vascular cell function in peripheral blood cells of patients with actual moyamoya disease.”

The research results were published in the ‘Journal of Cerebral Blood Flow and Metabolism’, an international academic journal in the field of cerebral blood flow and metabolism.

Meanwhile, the proportion of patients with the RNF213 gene mutation is approximately 80% in Korea and Japan.

Moyamoya disease is a rare, incurable disease in which the arteries that supply blood to the brain gradually narrow and eventually become blocked. When the blood supply to the brain becomes insufficient, abnormal microscopic blood vessels grow to compensate for this. Because these blood vessels resemble smoke, it is called ‘moyamoya’ disease, which means ‘sharp’ in Japanese.

Moyamoya disease has a high prevalence and family history in Asia, including Korea, Japan, and China. Therefore, genetic causes are assumed to be the main cause of the disease.

Daeik Kwon medical reporter [email protected]

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