Huntington's disease and blood vessels
Symptoms of Huntington's disease were associated with a change in gene expression
Natalia Kondratenko, N+1
A group of scientists from the USA sequenced the RNA of cerebrovascular cells obtained from healthy patients and patients with Huntington's disease. Experts found 4.5 thousand genes with differing expression, among which were genes responsible for endocytosis, the development of an inflammatory response and the formation of intercellular contacts. An article describing the study was published in the journal Nature (Garcia et al., Single-cell dissection of the human brain vasculature).
Huntington's disease is a neurodegenerative disease caused by mutations in the huntingtin protein gene. However, in addition to nerve tissue damage, Huntington's disease is also characterized by disorders in the cerebrovascular system — the system that provides blood supply to the brain. Among such disorders, it is worth highlighting the increased permeability of the blood-brain barrier (BBB), which should prevent the penetration of pathogens and harmful substances into the brain.
BBB consists of endothelial cells forming the inner lining of blood vessels, as well as astrocytes, pericytes and neuroglia cells. These cells are very closely adjacent to each other due to a large number of dense intercellular contacts, which provides a barrier function. Violation of the BBB function in patients with Huntington's disease is sometimes observed even before the onset of characteristic symptoms of the disease (these include chorea — erratic uncontrolled movements). However, the molecular mechanisms of these disorders are unknown.
A group of scientists from The Massachusetts Institute of Technology, led by Myriam Heiman, compared the expression profiles of the cerebrovascular system cells of healthy patients and patients with Huntington's disease. Based on the expression of specific markers, scientists isolated cerebrovascular cells from brain preparations, and then sequenced single cells. In total, 17 thousand cells were sequenced.
Sequencing revealed more than 4.5 thousand genes, the expression of which differed in healthy patients and patients with Huntington's disease. In particular, MFSD2A expression was suppressed in the endothelial cells of patients with Huntington's disease. The product of this gene suppresses caveolar endocytosis in BBB cells — the capture of substances by the formation of small vesicles. The authors note that it is the activation of endocytosis caused by the suppression of MFSD2A expression that may underlie the increase in BBB permeability. In addition, in patients with Huntington's disease, the expression of genes encoding proteins of dense intercellular contacts in the cells forming the BBB was reduced.
In the endothelial cells of patients with Huntington's disease, the expression of IKBKB, IRF2/3, and STAT3 genes responsible for the development of inflammation was increased. Increased expression of the genes involved in the inflammatory response was also observed in astrocytes and neuroglia cells.
Huntington's disease is not the only condition in which the integrity of the BBB is violated. Earlier, scientists found out that the BBB turns out to be permeable in those places where the cells forming it come into contact with neuronal stem cells.
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