Mutation in the HTT gene critically affects the cell motility and alter cytoskeleton organization in cultured dermal fibroblast of patients with Huntington's diseaseстатьяТезисы
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 24 января 2020 г.
Аннотация:Huntington's disease (HD) is a severe and currently uncurable hereditary autosomal dominant neurodegenerative disease, effected by the progressive death of the medium spiny neurons of the striatum, leading to death after 8-15 years since the manifestation. The cause of HD development is an expansion of CAG repeats in the gene of huntingtin protein (HTT). Despite the fact that this mutation has the greatest impact on neural cells, it is shown that HTT is expressed in all cells and tissues of mammals. The function of HTT in humans is not clear, however, it is revealed that HTT interacts with proteins involved in (1) transcription, (2) signal transduction in the cell and (3) intracellular transport. We investigated morpho-functional disorders occurring at the cellular level and affecting subcellular cytoskeletal structures (microtubules and actin components). The primary fibroblasts obtained from the skin biopsy of HD patients with different length of CAG repeats in the HTT gene (42, 44 and 76) were used as the object of the study. Fibroblasts from skin biopsies of healthy donors corresponding to patients by sex and age have been applied as control. Physiological tests showed that fibroblasts of HD patients have different characteristics of spreading and movement compared to fibroblasts from healthy donors. They have a shorter stage of spreading, are capable to polarize before complete cell spreading and start the movement before polarization stage is fully completed. Patient’s fibroblasts do not form a pronounced leading edge and tail at the stage of polarization, their lamella forms numerous thin outgrowths on the leading edge during the process of attachment and spreading on the substrate. During the experimental wound healing fibroblasts of HD patients moved faster than control cells, but their movement was more chaotic – they often changed direction of movement compared to normal cells. Confocal microscopy and SIM showed that the structure of the microtubule network does not change critically in the cytoplasm of HD fibroblasts . However, the architecture of cytoplasmic actin network changes and the mutual arrangement of γ - and β-actin structures is disturbed. Herewith the total amount of γ - and β -actin proteins does not differ from that in fibroblasts of healthy donors. In patient’s cells the process of formation of primary cilia is violated: the number of cilia was lower, and their average length was less than in fibroblasts of healthy donors. Thus, our results had shown for the first time that in Huntington's disease morphological disorders caused by mutations in the HTT gene affect the cell cytoskeleton structures, which leads to changes in cell spreading and motility. Supported by RSF (#19-15-00425) and MSU Development Program PNR 5.13.